House begins a detox program at Mayfield Psychiatric Hospital to get the Vicodin out of his system in an attempt to control his hallucinations. House being House, he tries to fool the doctors by not taking his medicine pretending he is getting better, but soon realizes that he has deep underlying issues. He starts his treatment and plans to leave the facility once he is clean, but he is strong-armed into staying by his attending physician, Dr. Darryl Nolan (Andre Braugher). Dr. Nolan agrees to write a recommendation to reinstate House's medical license only if House agrees to further treatment. When House is moved to a new ward in the hospital, he develops a close relationship with his new roommate, Alvie (Lin-Manuel Miranda), and Lydia (Franka Potente), a frequent visitor who helps House bend the rules. House asks Alvie to help him uncover incriminating information about Dr. Nolan that would allow him to blackmail his way out of the treatment center and convinces Lydia to loan him her car to sneak out a delusional patient in an attempt by House to undermine Dr. Nolan's course of treatment. But when devastating events ensue, House is humbled into reluctantly accepting help. After a delusional patient jumps off of a building, House decides that he needs to face himself and accept treatment from Dr. Nolan. He kisses Lydia at a party, Dr. Nolan helps him figure out what the kiss meant. After a catatonic patient, Lydia's sister-in-law, is cured, Lydia and her family decide to move to Arizona. House is eventually deemed healthy enough to leave Mayfield. As he does so, Alvie looks over his friend through a window. Inspired, he goes to a doctor, and requests meds, which he had not been taking, wanting to get better.

House returns and has surprising news for Cuddy; on the advice of his therapist, Dr. Darryl Nolan, he's quitting his job; an ailing video game creator (Rick D. Wasserman) opts for treatments suggested by people on the Internet rather than listening to the team, which is now being run by Foreman. Taub quits saying he only wanted this job to work with House. In the end, House wants to go back to his job in diagnosing, to help him ignore his leg pain. We learn that he is the one who solved Foreman's case. In the end Foreman fires Thirteen saying continuing to work together might drive them apart.

The team treats a controversial African politician named Dibala (James Earl Jones) who has fallen ill while coming to America to give a speech at the United Nations. Meanwhile, Wilson tries to make amends with a feuding neighbor. Fearing a planned genocide, Chase purposely mixes up the blood tests with that of a body in the morgue, causing Dibala to be treated for the wrong illness. The dictator is killed, leaving Chase and Foreman guilty.

Final diagnosis: Blastomycosis (Dibala) and Phantom limb (Murphy)

A wealthy businessman (Lee Tergesen) brings his son (Tanner Maguire), who is suffering from inexplicable stomach pains, to Princeton Plainsboro and insists on having Dr. House handle the case. The father of the patient believes the karmic penalty of his financial success is that he is victim to personal tragedy, and that the answer to his son's medical mystery lies in a reverse of fate rather than medical treatment. Meanwhile, Foreman and Chase prepare to present information on the Dibala case.

Final diagnosis: Primary Antiphospholipid syndrome

Cameron pushes the team to treat a man (Jon Seda) whose father, grandfather and great-grandfather have all died of a sudden heart attack before the age of 40, but House is reluctant to take the case without distinctive symptoms. Meanwhile, Chase is haunted by his actions in the Dibala case.

Final diagnosis: Intracranial berry aneurysm of the brain stem

After a wild night out, a teenage girl (Annabelle Attanasio) is brought to Princeton Plainsboro with severely swollen appendages. The team must work to diagnose the young girl, who is less than honest about what happened the night she fell ill. As her condition worsens, she becomes unable to distinguish fact from fiction. Meanwhile, Cuddy, Wilson and House spend a weekend away from the hospital to attend a medical conference, but things don't go as planned when House's private investigator, Lucas Douglas (Michael Weston), returns.

Final diagnosis: Vibrio vulnificus and haemochromatosis

After House's medical license is reinstated, he reclaims his role as Head of Diagnostics in time to treat Hank Hardwick (Troy Garity), an adult film star admitted to Princeton-Plainsboro for pulsating eye pain. Meanwhile, Cuddy is reminded that Princeton-Plainsboro is not conducive to healthy personal relationships. At the end of the episode, Cameron leaves the team and Chase.

On the eve of Thanksgiving, House and the team take on the case of James Sidas (Esteban Powell), an exceptionally brilliant physicist and author who traded his successful career for a job as a courier. For the ailing patient, intelligence is a miserable burden that has prompted depression and addiction, and this, coupled with myriad strange symptoms, nearly stumps the team. Meanwhile, the doctors at Princeton-Plainsboro wrestle with strained personal relationships.

Final diagnosis: Thrombotic thrombocytopenic purpura complicated by dextromethorphan abuse and multiple accessory spleens

An old friend and former patient (Joshua Malina) of Wilson's experiences paralysis in his left arm during a hunting trip. Wilson takes this case himself. House thinks his friend has leukemia like before, however Wilson stays optimistic until the worst happens. Now he is forced to make radical decisions. Cuddy continues her search for real estate.

Final diagnosis: Acute lymphoblastic leukemia

The team treat a man (Ethan Embry) who associates with drug dealers after he collapses during a sale, however the man refuses to reveal personal information to the team because it might incriminate him. Foreman's teammates conspire to convince him that his salary is less than theirs. Wilson buys a new condo, and House and Wilson are both flirting with Nora (Sasha Alexander), an attractive new neighbor in their building who thinks that House and Wilson are in a committed relationship.

Final diagnosis: Hughes–Stovin syndrome

The team takes on the case of Valerie (Beau Garrett), an attractive executive experiencing random episodes of excruciating pain. House agrees to take the case based on Valerie's looks, and while treating her, the men on the team are charmed by Valerie's beauty and personality, with Thirteen looking beyond the superficial to try to discover a link to her illness. Meanwhile, House uncharacteristically attempts to alleviate his conscience by reaching out to a former medical school colleague (Ray Abruzzo) he wronged.

Final diagnosis: Psychopathy secondary to Wilson's disease

House and the team rush to treat an ailing college American football star (Da'Vone McDonald) in time for the patient to compete in NFL tryouts. But when the patient experiences an onslaught of varied and unusual symptoms, the team has trouble reaching a consensus on how to effectively treat him in time. Meanwhile, Foreman's brother Marcus (Orlando Jones) makes a surprise visit to the hospital.

Final diagnosis: Paraneoplastic syndrome secondary to melanoma

During a day in the life of Princeton-Plainsboro's Dean of Medicine, Dr. Lisa Cuddy, the inner workings of the hospital are seen through her eyes. This day proves to be especially trying as Cuddy wrestles with myriad hospital issues and staff disputes that test her perseverance and skills as an administrator, all while juggling issues in her personal life.

The team treats a famous blogger (Laura Prepon) for sudden coagulopathy, but finds her difficult to treat when she insists on discussing all procedures and doctors on her blog. Meanwhile, House and Wilson learn secrets about each other and go speed dating along with Chase.

Final diagnosis: Whipple's disease

House and team tries to diagnose a high school senior (Cali Fredrichs) suffering from blackouts and hallucinations, and are forced to take a controversial approach. Meanwhile, Wilson attempts to furnish his new condo, and Taub brings his personal life into the workplace.

Final diagnosis: Cerebellar schistosomiasis delayed hypersensitivity allergy

The diagnostics team takes on the case of a man roleplaying as a knight (Noah Segan) who collapses at the end of a duel during a Renaissance Fair, leading Foreman and Thirteen to head to the fair to investigate. Meanwhile, House learns that Wilson's newest girlfriend is his ex-wife, and tries all means to ruin the relationship in order to protect his friend from being hurt again.

Final diagnosis: Anabolic steroid abuse accelerated by hemlock poison

A woman in an open marriage (Sarah Wayne Callies) suddenly becomes ill during a date with her boyfriend; House tests Wilson and Sam's relationship. Taub's wife gives him permission to have relationships with other women.

Final diagnosis: Henoch–Schönlein purpura

The team takes on the case of an ailing groom-to-be (Adam Garcia) who harbors undisclosed secrets from a previous relationship. As his fiancée (Eva Amurri) tries to get answers to her many questions, a frustrated team winnows down the possibilities. Meanwhile, House spends extracurricular time with his Princeton Plainsboro colleagues, performing a karaoke rendition of a Gladys Knight & the Pips classic with Foreman and Chase.

Final diagnosis: Arnold–Chiari malformation

House tells Dr. Nolan about the case of a woman (Zoe McLellan) suffering from both amnesia and another mystery condition. But Dr. Nolan believes that something else is troubling House — including the fact that Wilson is kicking him out of their home.

Final diagnosis: Allergic reaction to tattoo ink.

After a crane collapse buries a woman (China Shavers) beneath rubble, House must split his time between staying with her and diagnosing the crane operator (Doug Kruse) who passed out. But when she dies despite his best efforts, House must avoid the temptation to relapse on Vicodin—until Cuddy admits her love for him.