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. While his behavior can border on antisocial, House is a maverick physician whose unconventional thinking and flawless instincts have afforded him a great deal of respect. 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 Kindergarten teacher starts speaking gibberish and passed out in front of her class. What looks like a possible brain tumor does not respond to treatment and provides many more questions than answers for House and his team as they engage in a risky trial-and-error approach to her case. When the young teacher refuses any additional variations of treatment and her life starts slipping away, House must act against his code of conduct and make a personal visit to his patient to convince her to trust him one last time.
When a teenage lacrosse player is stricken with an unidentifiable brain disease, Dr. House and the team hustle to give his parents answers. Chase breaks the bad news, the kid has MS, but the boy's night-terror hallucinations disprove the diagnosis and send House and his team back to square one. As the boy's health deteriorates. House's side-bet on the paternity of the patient infuriates Dr. Cuddy and the teenager's parents, but may just pay off in spades.
A college student collapses after rowdy sex with his girlfriend. While House and his team attempt to determine the cause, the student's condition continues to deteriorate and his symptoms multiply complicating the diagnosis.
When a virus is spreading among the hospital, infecting six babies, House and his team must make decisions that could compromise the lives of the babies.
A nun whose hands are red, swollen and cracked is sent to House. The nun believes it is stigmata, but House suspects an allergic reaction. He gives her some pills, which cause her to become unable to breathe. As her condition worsens, her fellow sisters pray for her while House and his team work to discover the cause of her illness while House has to wonder if he misadministered the illness.
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.
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.
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.
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 get her a necessary transplant.
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.
At a high-level campaign fundraiser, a senator becomes violently ill. Vogler forces House to take the senator's case and offers to let off the hook on firing a team member if he'll deliver a speech on behalf of Vogler's pharmaceutical company. It looks like the senator has AIDS but House refuses to settle for the easy answer. And House ends up giving the speech, but it doesn't go quite as Vogler planned.
While House and his team scramble to discover what's causing brain and kidney dysfunction in a pregnant woman, Vogler is working to get House fired after House's pharmaeutical speech. House determines the illness, but the woman and her husband must struggle with an emotional and heartbreaking choice: choose between her or that of her unborn child. Vogler calls for a vote to remove House, but when Wilson refuses to make the vote unanimous, Vogler threatens to take his money if Wilson isn't voted out. Finally, Cuddy must take a stand against Vogler.
During an meningitis outbreak which overwhelms the clinic, House is drawn to a single patient: a 12-year-old whose symptoms don't quite match everyone else's. House, Foreman, and Chase must devise ingenious ways and locations to treat the girl's delicate condition in the middle of the chaos, and make an unexpected discovery. Meanwhile, House asks Cameron to come back to her job but she has one requirement that he might not be able to meet.
House apparently triggers a stroke in a clinic patient, but the major topic of discussion is House's imminent date with Cameron, The team must deal with the patient's odd lifestyle, overbearing "friend," and reluctant parents in order to stop the strokes and try to save his life. Meanwhile, Wilson, Cuddy and the team offer House and Cameron advice while laying odds on the outcome.
House's ex-girlfriend Stacy Warner returns – not for House but to get help for her ailing husband. While House decides whether or not to take her case, Cuddy forces him to present a lecture to a class of medical students. As he weaves the stories of three patients who all present with a similar symptom, House gives a lecture the students will never forget.
When Stacy insists her husband Mark get tests, House insists he can handle things. But despite the fact Mark's tests prove negative, his steadily growing symptoms indicate he is dying. While House struggles with the mystery and make increasing demands on his staff, Wilson worries about House's emotional well-being, and Cuddy considers adding a new employee to the clinic.