Dr. Gregory House is devoid of bedside manner and wouldn't even talk to his patients if he could get away with it. Dealing with his own constant physical pain, he uses a cane that seems to punctuate his acerbic, brutally honest demeanor. House's roster of medical cases are the inexplicable ones other doctors can't solve, and he has assembled an elite team of young medical experts to help him in his effort to solve these diagnostic mysteries.
A 29-year old preschool teacher (guest star Robin Tunney) collapses in her classroom from a seizure. She is taken to Princeton-Plainsboro Teaching Hospital, where Dr. House and his team of experts grapple to solve the mystery.
A 16-year-old high school student, Dan (Scott Mechlowicz), starts suffering from night terrors and frequent hallucinations, and he reveals he was hit in the head while playing lacrosse at school. Dan is apparently suffering from MS, and risky brain surgery is needed. Meanwhile House must deal with a patient looking to set up a lawsuit and a mother who does not believe in vaccinations.
Dr. House and his team struggle to find out why a college student (Kevin Zegers) collapsed after having sex with his fiancée.
House's prediction that two sick babies is the beginning of something worse is dreadfully correct and he and his team quarantine the hospital's maternity ward as they try to find out the source of the illness.
Dr. House's approach raises questions when he treats a nun for what he believes to be an allergy, and almost kills her.
When a schizophrenic mother has a deep-vein thrombosis, a strange phone call causes House to question her (in)sanity once again.
Two men are out jogging – one of them returns back to his wife who slaps him and says that she thinks she has something wrong with her and brings her to the clinic. 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.
House and his team investigate the mysterious poisoning of high-school student Matt Davis but another teen is brought in with all of the same symptoms but almost nothing else in common with Matt.
When a legendary jazz musician collapses mid-session, House and his team run into technical difficulties treating the man, who has amyotrophic lateral sclerosis, but when he orders to have a DNR, House disobeys it and ends up in court.
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. Meanwhile, House has an audience of two medical students who are learning how to do case studies.
While trying to figure out why a young patient will not stop bleeding after a car wreck, House takes 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 more and more severe, his patient directives for his patient are more harsh and risky than usual, and Foreman and Cameron are afraid he may not be thinking clearly enough to save the patient's life.
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 – 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 would have to abort her early pregnancy. Meanwhile, Foreman dates a pharmaceutical representative and House is stuck with an extra ticket to a monster truck rally.
After consulting a Ouija board on his life, a young boy thinks that he is going to die. Chase's father comes to the hospital to meet Wilson and help House to diagnose the kid.
Billionaire entrepreneur Edward Vogler spends $100 million on the clinic and becomes the new Chairman of the Board. As a businessman, Vogler intends to turn the clinic into a profitable venue for his biotech venture and plans to eliminate the financially draining services of Dr. House. Meanwhile, a businesswoman who has it all – perfect life, perfect body, perfect job – finds herself inexplicably paralyzed. When he diagnoses her secret, House must risk his job and his medical license to save her.
House is placed under a court order to discern what is ailing a mobster due for federal testimony and then the Witness Protection Program. The witness's brother and lawyer appears to work against the team and the testimony when they discover his brother has hepatitis C. Cuddy continues to battle Vogler over House's importance to the hospital.
House and his team investigate when an overweight ten-year-old girl has a heart attack. Adding to his stress, Vogler still demands that House get rid of one member of his team. His initial choice is rejected by Vogler and House believes that he is being sold out.
A popular U.S. senator 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 and team dig deeper for another answer. Meanwhile, House handles the case of a woman who apparently got pregnant without having sex.
A pregnant woman arrives at the hospital with brain and kidney problems and House must contend with both her condition and Vogler's eagerness to see the doctor removed. The couple are told they will have to decide between the mother and child's lives after the team discovers small cell lung cancer. Vogler calls a board meeting in order to get rid of House.
House fights off a meningitis outbreak and Cuddy gives his team an hour to produce results after he singles out a young patient who does not quite fit the criteria. House tries to get Cameron to return in the wake of Vogler's departure but she asks House to tell her why he really wants her back.
The teaching hospital buzzes with rumors of House's upcoming date with Cameron. House is harsh to a patient, and when he tries to apologize, the patient has a stroke. House also deals with an elderly couple who partake in the little blue pill.
House receives a visit from an ex-girlfriend, who has come seeking his help for her husband. House gives a lecture to medical students about diagnosing patients and presents three patients that have three different reasons for their leg pain. (guest star Carmen Electra)
House diagnoses Mark, the husband of his former love Stacy. Although the tests do not indicate a condition and he claims to be fine outside of stomach pain, it appears that his brain is dying which leaves House puzzled. When he comes to a potential diagnosis, he has to fight against the patient's wishes to get the proper test done.