Rebecca Adler (Robin Tunney), a 29-year-old kindergarten teacher, becomes dysphasic and collapses in her classroom. Dr. Gregory House initially refuses the case until Dr. James Wilson tells him that Rebecca is his cousin. When Dr. Lisa Cuddy tries to make House fulfill his clinical duties, he refuses but is forced to do them when his authorization to the MRI is revoked. He diagnoses Rebecca with cerebral vasculitis and her condition improves with treatment. To find the source of Rebecca's seizures, House convinces Dr. Eric Foreman to break into Rebecca's house. At the hospital, Rebecca suddenly loses her vision and suffers another seizure. Foreman discovers ham at Rebecca's house, revealing both Wilson's lie (Wilson is Jewish and the presence of ham indicates Rebecca is not, thereby suggesting the two are not related) and the cause of the seizure—tapeworms (namely, a tapeworm larva embedded in her brain). When Rebecca refuses treatment, House persuades her otherwise by proving her condition with a non-invasive X-ray suggested by Dr. Robert Chase, which depicts a tapeworm larva embedded in her leg, supporting their diagnosis.

A 16-year-old high school student, Dan (Scott Mechlowicz), starts suffering night terrors and frequent hallucinations after playing lacrosse at school. Dan's parents take him to see Dr. House after receiving a letter that Cameron sent in House's name. Upon meeting the family, House begins a bet to determine whether they are his biological parents. After Dan exhibits more symptoms, including a myoclonic twitch and a blocked blood vessel, House diagnoses Dan. Dan suffers from an auditory hallucination during a procedure, however, ruling out House's diagnosis. Using coffee cups from the parents, House does an unauthorized paternity test and discovers that neither parent is biologically related to Dan. House flashbacks to a case he had earlier that involved a mother who did not want her baby to be vaccinated and theorizes that Dan is suffering from a measles virus contracted during his childhood. House confirms his diagnosis with a retinal biopsy and successfully cures Dan.

A college student named Brandon (Kevin Zegers) collapses after having sex with his fiancée. His symptoms seem too numerous to be explained by just one disease. Foreman and House each suggest different diagnoses and argue that his own respective theory better conforms to Occam's Razor. But then Brandon's white blood cell count drops, proving both doctors wrong. At the clinic pharmacy, House theorizes that the pharmacist accidentally gave Brandon colchicine instead of cough medicine, which explains all of his symptoms aside from his cough. House gives Brandon the cure, and he immediately begins to recover, though nobody believes the pharmacist made a mistake. However, when Brandon comments that his old cough medicine did not have letters on it like his current pills, House discovers colchicine pills that look similar to cough medicine, revealing the source and confirming House's diagnosis.

After overhearing a conversation about a sick baby, House investigates the maternity ward and predicts an epidemic. After realizing the severity of the disease, Cuddy quarantines the maternity ward. In an effort to discover the source of the epidemic, House begins treating the children. However, when the kidneys of two of the children shut down, House is forced to test which drug caused the failure, resulting in one of the babies dying. Following an autopsy, the team discovers the presence of echovirus 11, CMV, and parvovirus B19antibodies. They test the mothers and decide the cause of the epidemic is the Echovirus. Using an experimental anti-virus, they successfully cure the remaining babies. House, determined to find the entry point of the virus, finds an elderly hospital volunteer coughing and wiping her nose as she pushes around a cart of baby toys and blankets and makes the connection.

Sister Augustine (Elizabeth Mitchell) arrives at the hospital with her hands covered in severe rash, which her fellow nuns think looks like stigmata and which House diagnoses as dermatitis caused by a dish soap allergy. When the antihistamines he gives her cause an asthma attack, House administers epinephrine, and she suffers a minor heart attack. House's team suspects that House made a mistake with the epinephrine, but when they try to find the source of her problems, she suffers hallucinations, convulsions and a rash appears on her leg. Cuddy pulls House off of the case when she hears of House's methodology. An investigation of the convent reveals figwort tea, which explains only the reaction with the epinephrine. She is placed in a hypoallergenic room but inexplicably still has an allergic reaction. But when she begins shouting that she has God inside her, it allows House to find a copperIUD inside her uterus. The device is surgically removed and she fully recovers.

A mother, Lucille Palmeiro (Stacy Edwards), collapses after a blood clot travels from her leg to her heart. After arriving in the hospital, she begins to vomit blood, causing House to expect a Vitamin K deficiency. House's team discover unused Ampicillin and frozen microwave burgers, supporting House's diagnosis. An ultrasound of Lucille's liver reveals cirrhosis and a cancerous tumor. House treats the tumor with ethanol, but is unable to explain the cirrhosis. However, Lucille, in a decision House claims to be inconsistent with her schizophrenia, calls Social Services to take her son. House realizes that Wilson's disease explains the cirrhosis and an eye exam shows copper-colored rings around her irises. Lucille receives treatment, is healed, and reunites with her son.

After returning from jogging with his best friend, Ed (Dominic Purcell) is uncharacteristically abused by his bedridden wife. House concludes that she either has Rabbit Fever from cooking rabbits or African Sleeping Sickness, which must have been sexually transmitted since neither of them has been to Africa. They both strongly deny having an affair so House starts treatment for Rabbit Fever. When this fails he successfully treats her for Sleeping Sickness. She confesses to an affair with her husband's best friend, causing her husband to leave her.

House and his team investigate the mysterious poisoning of high-school student Matt Davis (John Patrick Amedori), until another teen is brought in with all of the same symptoms but almost nothing else in common with Matt. Eventually it is discovered that both youths bought very cheap pairs of jeans at a car boot sale. The jeans were exposed to high doses of pesticides. Meanwhile, House has an old lady hit on him who turns out to have Neurosyphilis.

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John Henry Giles (Harry Lennix), a legendary jazz musician with ALS, is brought in to be treated by Foreman for pneumonia. House's attempt to prove that he doesn't really have ALS causes John Henry to suffer respiratory failure. House intubates him in violation of his DNR and tries to keep him on life support using a legal technicality. Cameron notices a blood clot, which is removed, and MRI reveals an Arteriovenous malformation which is operated on restoring his ability to walk. Meanwhile, Foreman receives a lucrative job offer from John Henry's doctor, his former mentor.

Dr. Foreman believes an uncooperative homeless woman (Leslie Hope) is faking seizures to get a meal ticket at the hospital. But her situation strikes a chord with Dr. Wilson and he resolves to keep her from falling between the cracks. Meanwhile, House gets an audience of two medical students who are learning how to conduct medical histories.

While trying to figure out why a young patient (Nicholas D'Agosto) will not stop bleeding after a car wreck, House accepts Cuddy's challenge and goes off Vicodin for a week in exchange for no clinic duty for a month. As House's withdrawal symptoms become severe, his methodology for his patient are more harsh and risky, and Foreman and Cameron are afraid he may not be thinking clearly enough in order to save the patient's life. House does solve the case though by exhuming the family's recently deceased cat and performing an autopsy on it. He finds high doses of napthalene, which is excreted by termites as a repellent. The patient has been exposed to the poisonous vapors due to a termite nest behind the walls of his bedroom

A severely broken arm reveals a bizarre case of bone loss and ends the comeback plans of major league pitcher Hank Wiggen (Scott Foley). House suspects Hank – with a history of drug abuse – is lying about using steroids, as his condition worsens. When Hank's kidneys start to fail, his wife offers to donate hers, but she will have to abort her early pregnancy, something Hank does not want. Eventually House finds out the wife suffers from loss of smell, indicating the pair have smoked cannabis which was grown on cadmium polluted soil. Meanwhile, Foreman dates a pharmaceutical representative and House goes to a monster truck rally with Cameron.This episode features a cameo appearance by the series' director and executive producer Bryan Singer.

After consulting a Ouija board, a young boy (Daryl Sabara) believes he is going to die, and is sent to Princeton-Plainsboro after suffering from pneumonia. Meanwhile, Chase's estranged father (Patrick Bauchau) comes to the hospital and helps House and his team diagnose the kid.

Billionaire entrepreneur Edward Vogler (Chi McBride) donates $100 million to Princeton-Plainsboro, officially becoming the new Chairman of the Board. Vogler intends to turn the clinic into a profitable venue for his biotech venture and also plans to eliminate House's financially draining department for good. Meanwhile, a businesswoman (Sarah Clarke) has it all – perfect life, perfect body, perfect job – until she finds herself inexplicably paralyzed. When he diagnoses her condition, House must risk his job and his medical license to save her.

House is placed under a court order to determine what is ailing a mobster (Joey Arnello, played by Joseph Lyle Taylor) due for federal testimony and the Witness Protection Program. The witness's brother, a lawyer, works against the team and the testimony when his brother is diagnosed with Hepatitis C. Cuddy continues to battle Vogler over House's importance to the hospital.

House and his team investigate an overweight ten-year-old girl (Jennifer Stone) who has a heart attack and her mother (Cynthia Ettinger) insists that House and his team look past her weight to find the diagnosis. Adding to his stress, Vogler demands House get rid of a member of his team.

A popular U.S. senator (Joe Morton) and presidential candidate succumbs to illness at a fundraiser and Vogler assigns House to his case. He also tells House he can keep his whole team if he endorses Vogler's pharmaceutical company. The Senator's initial diagnosis seems to point to AIDS, but House digs deeper for another answer. Meanwhile, he also handles a case of a woman who apparently gets pregnant without having sex. Cameron leaves the team and quits.

A pregnant woman (Marin Hinkle)^[27] arrives at the hospital with brain and kidney problems and House must contend with her condition and Vogler's eagerness to see the doctor removed by using the board members. The patient and her husband must decide between her life and their unborn child's, after the team discovers small cell lung cancer.

Final diagnosis:LEMS secondary to small cell lung carcinoma

House fights off a meningitis outbreak and Cuddy gives his team an hour to produce results after he singles out a young patient (Skye McCole Bartusiak)^[29] who does not quite fit the criteria. House tries to get Cameron to return in the wake of Vogler's departure, but she demands House tell her why he really wants her back.

The hospital buzzes with rumors of House's upcoming date with Cameron. After House is harsh to an awaiting clinic patient (John Cho), the man develops a mysterious stroke. At the same time, House also deals with an elderly couple whose overactive sex life is seemingly causing them problems.

House receives a visit from an ex-girlfriend, Stacy Warner, who seeks his help for her husband, Mark. In the meantime, Cuddy forces House to give a lecture to medical students on diagnosing patients and presents three scenarios, each with different reasons for their leg pain (with guest star Carmen Electra).

House diagnoses Mark (Currie Graham), Stacy Warner's husband. Although the tests do not indicate a condition and Mark claims to be fine outside of stomach pain, it appears his brain is dying. House finds abdominal epilepsy, but cannot detect any memory loss. After Mark begins developing paralysis, House decides to treat him for Guillain–Barré syndrome. After confiding in Stacy that he still has feelings for her, House realizes that Mark had experienced delusions, and actually suffered from acute intermittent porphyria (AIP). With support from Stacy, but not from his team, House gives Mark a dangerous drug cocktail to confirm that he really has AIP. Cuddy decides to hire Stacy as the hospital's lawyer.

• Bonus Featurettes:
  • Dr. House
  • Medical cases
  • Casting session with Hugh Laurie
  • The Concept
  • Set Tour
  • House-isms