As the fifth season opens, Wilson returns from an extended leave following Amber's death and announces he's leaving Princeton-Plainsboro. House thinks it's a terrible idea, and he isn't shy about saying so. Wilson's announcement also distracts him from the case at hand, that of the workaholic 37-year-old assistant to the leader of a major feminist organization who collapses during a business meeting. Thirteen takes a special interest in the case, and House questions her reasons for doing so.
When people who received organs from a donor who was killed in an industrial accident five years earlier die suddenly, House must figure out why to save a recipient who's still alive. To track down information about the donor and the dead recipients, House hires a PI named Lucas (Michael Weston). But House also uses Lucas to snoop on Wilson as well as a colleague House is considering to replace Wilson as his friend.
A struggling artist (Breckin Meyer) taking part in three drug trials to pay his bills is also suffering from something that's altering his perception and threatening not only his livelihood but his life as well. Meanwhile, House has Lucas (Michael Weston) look into the private lives of his team, including Taub, whose marriage is in trouble.
House learns that his father (R. Lee Ermey) has died but must be coaxed into attending the funeral. Back at the hospital, the team struggles to treat a young Chinese-American adoptee who collapsed in China while searching for her birth parents, and House has to diagnose her over the phone. Meanwhile, flashbacks recall House's first meeting with Wilson. Blythe House: Diane Baker.
A woman with whom Thirteen had a one-night stand has a seizure at Thirteen's apartment, prompting intense curiosity (both professional and otherwise) about the women's personal lives from House and Foreman. Adding to the intrigue: Thirteen discovers why the woman wanted to sleep with her. Meanwhile, Lucas (Michael Weston) continues to snoop on Wilson.
A middle-aged single father who tests consumer products for a living and has been suffering unexplained blackouts turns out to be a sleepwalker. And soon his daughter falls ill as well. Meanwhile, Cuddy plans to adopt a child, but her birth mother falls gravely ill two weeks before her due date.
House and the team make a house call when an agoraphobe won't leave his home, but the patient's deteriorating condition makes it imperative to get him to a hospital. Meanwhile, House copes with a troublesome itch, and Cameron and Chase continue to refine their relationship.
During an examination of a teen's heart problems, the team begins to doubt her claims of being an emancipated minor. Meanwhile, Foreman defies House's rejection of a proposal to conduct a clinical trial.
A gun-wielding clinic patient (Zeljko Ivanek) takes House, Thirteen and several other patients hostage in Cuddy's waiting room and demands that House diagnose and treat him. The hostage taker also demands that House use other patients as guinea pigs for any medication he is going to receive. Thirteen volunteers for the treatment.
A fitness guru known for her "natural" lifestyle collapses while shooting an infomercial. Meanwhile, Thirteen participates in a clinical drug trial for Huntington's disease led by Foreman; Kutner operates an online medical-advice clinic under House's name; and Cuddy moves into House's office while hers is being repaired, much to House's dismay.
A troubled teen collapses during her high-school Christmas program; Foreman and Thirteen learn more about each other as they work together on the Huntington's disease drug trial; House gives and receives holiday gifts, leading to team speculation; and Cuddy receives a gift as well. Janice: Lori Petty.
At Cameron's urging, the team takes the case of a suicidal man who suffers from excruciating chronic pain---pain that mirrors House's. Meanwhile, Cuddy discovers that caring for her newly adopted baby leaves her little time to run the hospital; and Foreman and Thirteen continue to explore their complicated relationship as they work together on their Huntington's disease drug trial.
When Cuddy decides to spend more time caring her baby, she hands some of her day-to-day responsibilities to Cameron. One of them is supervising House, whose patient is a very nice special-education teacher who collapsed in class. House doesn't think that her niceness is a good thing. Meanwhile, Foreman must make a critical decision regarding Thirteen's participation in the Huntington's drug trial.
A woman who collapses during a cooking class turns out to be a renowned cancer researcher who gave up her career to pursue personal fulfillment. This prompts the docs to grapple with their own pursuits of happiness. Meanwhile, Cuddy decides to make House's life more miserable than it usually is, and Thirteen's health takes a turn for the worse.
A priest who runs a homeless shelter is admitted to the ER after seeing a bleeding Jesus hovering at his doorstep. House takes the case to distract the team while he confronts Foreman and Thirteen about their relationship, but it causes House to grapple with his past and his beliefs.
When a teen collapses with severe pelvic pain after playing basketball, tests reveal both male and female DNA. The parents knew this, but not the youngster. Meanwhile, Cuddy and Wilson suspect something is wrong with House when he begins acting nicely.
A book editor (Jay Karnes) suddenly begins insulting coworkers at a dinner party then falls ill. His loss of inhibition continues at the hospital, and this inability to lie affects his relationships with people close to him. Meanwhile, House suspects that Wilson and Taub are hiding something from him.
A nursing-home worker (Judy Greer) is alarmed when the home's cat curls up next to her. It seems that this cat cuddles up only to people who are going to die soon. Meanwhile, a financially strapped Taub reconnects with an entrepreneurial friend from high school.
After being hurt in a motorcycle accident in New York State, House shares a hospital room with a bicycle-accident victim (Mos Def) who's unable to move or communicate in any way. He has locked-in syndrome, House tells the doctors treating them both (more often than they want to hear), then he gets the man transferred to Princeton Plainsboro (these segments are told from the patient's point of view). Meanwhile, House won't tell Wilson why he was in New York, arousing Wilson's suspicions.
An older woman (Colleen Camp) who has spent the last six months caring for her dying husband (Meat Loaf) collapses from respiratory failure, and her condition only worsens in the hospital. But her husband's condition begins to improve.
House reluctantly takes the case of an environmental activist who collapsed at a protest demonstration, and the doc assigns much of the work on it to Cameron, who had urged him to take the case in the first place. Meanwhile, House has doubts about Wilson's healthy new diet.
A deaf 14-year-old says he heard explosions just before collapsing during a school wrestling match. When his condition worsens, his mother (Clare Carey) won't allow cochlear implants. Meanwhile, House's insomnia is playing tricks with his mind, but that doesn't seem to bother him.
The lungs of a ballerina (Jamie Tisdale) collapse while she's on stage, and her initial treatment causes her skin to fall off. Meanwhile, House not only still can't sleep, but he remains haunted by visions of Amber (Anne Dudek).
Season 5 finale: The team must deal with a patient (Ashton Holmes) whose brain is at war with itself (left side vs. right side). Meanwhile, House refuses yet again to work in the clinic, so Cuddy foists an unusual patient (Carl Reiner) on him. Amber: Anne Dudek.