House and Cuddy take the day off to talk about their new relationship, while the team tries to cure the lone neurosurgeon (George Wyner) on staff who must be ready to operate. If not, the hospital will have to shut down its ER and ICU. During the case, Thirteen prepares for her leave of absence.

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Final diagnosis: Toad egg toxicity

The team treats a teen skateboarder (Alyson Stoner) who collapsed during a competition, and her family must make an impossible decision. Meanwhile, House reveals his relationship with Cuddy to his team, and they both worry whether they can keep their work lives and love lives separate.

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Final diagnosis: Sickle cell trait

Absent: Olivia Wilde as Remy "Thirteen" Hadley

House and his team race against time to help an author (Amy Irving) who suffered a seizure while attempting to kill herself. With time running out until her psychiatric hold is over and she is released, House believes a clue may be found in her newest manuscript. Meanwhile, House tries to find what common interests he shares with Cuddy, and they double date with Wilson and Sam.

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Final diagnosis: Trauma-related syringomyelia

Absent: Olivia Wilde as Remy "Thirteen" Hadley

House and the team treat a woman (Erin Cahill) suffering from severe vomiting, heart problems, and a fever, but in the course of treatment, the team discovers that she is not who she says she is. During the case, House's new fellow (Vinessa Shaw), a psychiatrist that Chase hired, is welcomed with a trial by fire. Meanwhile, a visit from House's masseuse (and former hooker) forces him and Cuddy to confront the fact they are both holding back in their relationship.

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Final Diagnosis: Side effects of risperidone; schizophrenia

Absent: Olivia Wilde as Remy "Thirteen" Hadley

When a newborn experiences breathing problems, the team must look at her mother's (Jennifer Grey) medical history for clues, and what they find leads the mother to a difficult decision. Meanwhile, Foreman and Taub must both find a female replacement for Thirteen, and House and Wilson learn valuable lessons in babysitting when Cuddy has to work late.

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Final Diagnosis: Abbey: Pulmonary embolism secondary to lung cancer and melanoma. Abbey's baby: hereditary melanoma

Absent: Olivia Wilde as Remy "Thirteen" Hadley

Brilliant medical student Martha M. Masters (Amber Tamblyn) joins the team at Cuddy's insistence, and her first case is treating a campaign manager (Jack Coleman) who falls ill with a rash, leading to liver failure. But Masters' morality puts her at odds with House and the rest of his team. Meanwhile, House debates whether it is worth lying to Cuddy if it will save his patient's life.

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Final Diagnosis: Hepatitis C

Absent: Olivia Wilde as Remy "Thirteen" Hadley

A teenage girl (Hayley Chase) comes to the hospital displaying classic smallpox symptoms, which the team dismisses as impossible until her step-father (Andrew Fiscella) gets sick as well. Once the CDC intervenes and isolates the patients, the team is unable to explore any further until House takes a life-threatening risk.

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Final Diagnosis: Rickettsialpox

Absent: Olivia Wilde as Remy "Thirteen" Hadley

House must battle disease as well as belief when his patient (Kuno Becker) gets sick after crucifying himself as part of a bargain with God to keep his daughter cancer-free. But when this bargain causes him to refuse treatment, House must devise a new tactic. Meanwhile, Taub sees the other side of indiscretion, and Wilson and Sam's relationship changes.

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Final Diagnosis: Marburg multiple sclerosis and Rhodococcus equi infection secondary to malnutrition

Absent: Olivia Wilde as Remy "Thirteen" Hadley

When a bassist (Matthew Lillard) passes out after saving a woman in a subway station, the team must treat him amidst his newfound celebrity, while he begins to realize he may be a better man than he believed. Meanwhile, House must survive a dinner with Cuddy's mother (Candice Bergen), and Taub comes to terms with his marriage after he is featured in an ad for the hospital.

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Final Diagnosis: Chickenpox

Absent: Olivia Wilde as Remy "Thirteen" Hadley

A drill sergeant (Sasha Roiz) at a camp for troubled kids collapses with severe back pain, and House and the team must find a connection when one of his recruits (Tyler James Williams) falls ill with the same symptoms. Meanwhile, Chase must track down whoever is pranking him through a social networking site, and House tries to help Rachel get into a prestigious preschool.

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Final Diagnosis: Variegate porphyria

Absent: Olivia Wilde as Remy "Thirteen" Hadley

Cuddy's mother (Candice Bergen) is rushed to the hospital with heart problems, but refuses treatment by House. When he discovers what is killing her, House, his team, and Cuddy risk their careers to give her the treatment without Cuddy's mother or her doctor finding out. During the case, Masters weighs the dangers of coming clean versus keeping quiet. Meanwhile, Taub risks his side job working for his ex-brother-in-law to correct what he deems to be a medical oversight.

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Final Diagnosis: Cobalt poisoning secondary to metallosis

Absent: Robert Sean Leonard as James Wilson and Olivia Wilde as Remy "Thirteen" Hadley

A woman (Tina Holmes) comes to the hospital with temporary paralysis, but it is her perfect memory which compels House to take the case. Meanwhile, Taub prepares for an exam which is vital to his career, and Wilson's new companion has House concerned.

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Final Diagnosis: McLeod syndrome causing obsessive–compulsive disorder

Absent: Olivia Wilde as Remy "Thirteen" Hadley

House attends a career day at an elementary school as a favor so Rachel can get accepted. Most of the class becomes fascinated with the case of a man (Willis Chung) who literally coughed up a lung, but things soon get out of control. As House waits for the principal, two students (Austin Michael Coleman & Haley Pullos) prod House into talking about love, and specifically, why Cuddy is angry with him.

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Final Diagnosis: Food lodged in the lung

Absent: Olivia Wilde as Remy "Thirteen" Hadley

A real estate higher-up (Adrian LaTourelle) is admitted to the hospital with a severe rash, but it soon becomes clear that he does not live the life that he has led his wife to believe. Meanwhile, House grapples with the fact that his relationship may be distracting him and affecting his ability to diagnose his patients.

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Final Diagnosis: Cryopyrin-associated periodic syndrome (specifically Muckle–Wells syndrome)

Absent: Olivia Wilde as Remy "Thirteen" Hadley

When Cuddy is admitted to the hospital with what may be life-threatening symptoms, House is confronted with the fact that he is not the supportive boyfriend Cuddy needs him to be, and her surreal dreams (including a scene choreographed by Mia Michaels) may be trying to tell her something about her relationship with House. Meanwhile, the team treats a student (Brett DelBuono) whose emotional scars run deeper than his physical ones, and Taub must decide if the student is a threat to others, or a kid struggling to find his way.

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Final Diagnosis: Ryan: Staphylococcus from an abscess. Cuddy: Benign tumor in the kidney; antibiotic allergy

Absent: Olivia Wilde as Remy "Thirteen" Hadley

Newly single and back on Vicodin, House gives himself the five-star treatment but begins to worry that nothing – not even medical puzzles – can excite him anymore. Meanwhile, he and his team treat a professional bullrider (Chad Faust) who got attacked by a bull after suffering a seizure. But because of his many previous injuries, the team must devise new diagnostic techniques, while Masters becomes quite attached.

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Final Diagnosis: Bartonellosis

Absent: Olivia Wilde as Remy "Thirteen" Hadley

A homeless man (Chris Marquette) is taken to the hospital after suffering a burn, but his condition quickly worsens. What intrigues the team, however, is the fact that he steadfastly refuses to give any information about his real identity. But when the truth of who he really is comes out, it leaves the team stunned. Meanwhile, House agrees to a sham marriage with a prostitute (Karolina Wydra) so she can get her green card, and Cuddy feels guilty for dumping House.

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Final Diagnosis: Refsum disease

Absent: Olivia Wilde as Remy "Thirteen" Hadley

House discovers that Thirteen has been in prison for the past six months, and attempts to discover what crime she was guilty of, while also enlisting her help in defeating his spud gun nemesis (Justin Chon). Meanwhile, the team takes the case of a teacher (Terry Maratos) who is coughing up blood. When they search his home, they find it filled with garbage. But even more disturbing is finding his wife (Kimberlee Peterson) living beneath the filth.

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Final Diagnosis: Nina: Ehlers–Danlos syndromes leading to compulsive hoarding; Q fever. Brian: Q fever

Absent: Lisa Edelstein as Lisa Cuddy and Robert Sean Leonard as James Wilson

Thirteen returns as Masters prepares to graduate. Her final case is that of a teenage girl (Michelle DeFraites) aiming to become the youngest sailor to circumnavigate the globe. As the case progresses, House offers Masters an internship in return for forging her lab work requirements. Initially refusing to compromise her integrity, she declines. But when her patient takes a turn for the worse, she must make a decision: her principles, or her patient's life?^{[lower-alpha 1]}

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Final Diagnosis: Lymphoid sarcoma (Lymphosarcoma)

The team takes on the case of a lottery winner (Donal Logue) suffering from paralysis and multiple types of cancer, and they must figure out if it is his new millionaire lifestyle that is making him sick. Meanwhile, Cuddy's mother threatens to sue the hospital over her treatment, and Foreman and Chase make a bet over who is repressing the uglier side of his personality more.

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Final Diagnosis: Teratoma

After losing a bet with Wilson over a boxing match, House is convinced that the fighter he bet on (Kevin Phillips) has an underlying medical condition that cost him the fight. While he tries to prove it, he leaves his team alone to help a bomb scientist (Linda Park) who suffered a seizure. Meanwhile, House may be experimenting with a new drug to help his leg pain.

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Final Diagnosis: Wendy: Spanish fly (cantherides) poisoning; Terry: Glomus tumor

When House discovers that the experimental drug he has been using causes fatal tumors, he decides to excise them himself. He attempts to do it in his bathtub but fails and calls around for help, with Cuddy being the only one to respond. Meanwhile, Thirteen's friend from prison (Amy Landecker), a relapsed drug user, arrives at her apartment needing medical care after being stabbed. With her friend unwilling to go to the hospital, Thirteen finds herself in trouble when the friend loses sensation and movement in her arm. Chase helps her out, brushing Thirteen's ego aside. Taub receives some unexpected news that could change his life.

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Final Diagnosis: Entamoeba microbial cyst (referred to as an Amoebic parasitoma)

The team treats a seriously ill performance artist (Shohreh Aghdashloo) who deliberately induced additional symptoms in herself with the aim of turning the diagnostics department into her new masterpiece, as House must decide which of her symptoms are real, and which are self-inflicted. As the case progresses, House vows to make changes in his life, but remains rooted in old habits. After the case is over, House, finally, deals poorly with his anger over the breakup and lashes out by driving through Cuddy's dining room and escaping to a beach.

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Final Diagnosis: Granulomatosis with polyangiitis (referred to by its former name "Wegener's granulomatosis" in the episode)

Final appearance of: Lisa Cuddy.