Just before mobster Joey Arnello spills the beans in federal court and enters witness protection, he collapses. A court order instructs House to find out if he's faking. House and his team struggle to diagnose and cure Joey while Joey's brother Bill tries to slow things down and keep Joey from testifying. Meanwhile, Cuddy struggles to convince Vogler that House is an essential part of the hospital.
House must fire one of his doctors and leaves them to think about it while they deal with an overweight 10-year old child who suffered a heart attack as the result of taking diet pills. House is also faced with a woman who won't accept surgery for a 30 lb. tumor because she wants to remain overweight.
House has to find out why a patient has internal bleedings after a car crash. In the meantime, he has a wager with Cuddy he can stay off the painkillers. Will his withdrawal symptoms eventually kill his patient?
A severely broken arm reveals a bizarre case of bone loss and ends the comeback plans of major league pitcher Hank Wiggen. House suspects Hank is lying about using steroids, as his condition worsens. When Hank's kidneys start to fail, his wife offers to donate hers, but she would have to abort her early pregnancy. Forced into an impossible solution, and admitting failure as an addict, Hank tries to take his own life. House and his team must isolate and fix the problem soon if this pitcher's life, as well his career, can be saved. Meanwhile, Foreman dates a pharmaceutical representative and House is stuck with two tickets and ends up going on a "date" with Cameron...to a monster truck rally.
A 12-year-old boy believes he's cursed after a Ouija board tells him he's going to die, and his father makes increasing demands on House as they try to diagnose the boy's pneumonia-like symptoms and incongruous rash. Meanwhile, Chase's estranged father, a renowned doctor from Australia, visits and House invites him to sit in, much to Chase's discomfort. When House diagnoses the boy's illness, the young patient is forced to face the idea that his father may not be everything he believes.
Legendary jazz musician John Henry Giles is checked into the hospital and when he's told he's dying from ALS, he signs a DNR to avoid a slow death. House disagrees with the diagnosis and goes against everyone's wishes when he violates the DNR to save Giles' life. The decision lands House in court, drives Foreman to consider taking another job, and results in Giles' paralysis worsening. But when the patient inexplicably starts getting better, the team has to figure out the mystery in reverse and find out why his condition is improving.
Dr. Foreman believes an uncooperative homeless woman is faking seizures to get a meal ticket at the teaching hospital. But her homelessness strikes a personal chord with Dr. Wilson and he grows determined to keep her from falling between the cracks. Her worsening symptoms prove to be a complex mystery for House and his team, but the mystery of her identity and medical history may hold the answers to saving her life. Just as the team suspects she has contagious meningitis, the woman goes missing, only to be tasered by the police, who bring her back. But House deduces the taser may have proven yet another diagnosis, with dire results. Meanwhile, House has an audience of two medical students who are learning how to do case studies.
Dr. House is intrigued by the symptoms of a schizophrenic woman, who displays mixed symptoms, including a tumor, but soon realizes the source of her problems isn't the obvious. House confronts his birthday and Chase confronts his past when the mother's son tries to keep up with her condition.
After being discovered dead asleep, a woman is admitted to the hospital. The doctors are puzzled by her symptoms, as they consider everything from tumors to breast cancer to rabbit fever. When all the treatments fail, House concludes she has African sleeping sickness. However, neither the woman nor her husband could possibly have ever been to Africa. The woman will die without the proper treatment, but neither one will admit to having an affair.
When a high school student falls victim to a mysterious but lethal poisoning, House and his team jump in to find out what is killing the teen. Suddenly, a second unrelated student is admitted with identical symptoms. With the boys' lives hanging in the balance, House and the team have to connect the dots fast. Meanwhile, an 82-year-old patient has become enamored with House while he helps her figure out the basis of her renewed fascination with her sexual feelings.