House is serving out a lengthy prison sentence for his various misdeeds, including his trip outside the country in an attempt to escape responsibility. Entirely cut off from his old life, House determines his current problems are the result of his inability to deal with people. Feeling he will never be able to practice medicine again, he plans instead to go back to university to earn a doctorate in physics - a field that will all but assure his isolation from other human beings.

A surprising visitor makes House an offer he can't refuse by giving him the opportunity to help the Princeton Plainsboro team treat a unique patient in order to save the life of an organ recipient being treated by Wilson. Although House finds himself back on familiar ground, he quickly realizes that much has changed since he left, and he is forced to work on the case with smart yet timid resident Dr. Chi Park. After several inconclusive treatments and with time running out, House and Dr. Park are left with one last option to examine the patient's medical history that could compromise House's conditional agreement with the hospital. Meanwhile, House makes an effort to reconnect with Wilson despite a cold reception.

House and Park treat a patient, Benjamin, who collapsed after making a surprisingly large charity donation, and come to suspect that the altruistic behavior is a symptom of a deeper disorder. When the patient offers to donate an organ for another patient, the doctors must convince Dr. Adams to help them confirm whether Benjamin is in his right mind or not.

A CEO falls mysteriously ill just days before he signs a contract that would relocate his company's entire labor force to China. House attempts to make an underhanded business transaction with his wealthy patient, but when the patient's condition worsens, the team must work around the clock to save his life. Meanwhile, Park prepares for her hearing with the Princeton Plainsboro Disciplinary Committee chaired by Foreman, and Adams' outlook on her patient's business venture reveals her deeper feelings about loyalty.

A man well-respected in his community suddenly collapses, and in the process of diagnosing his symptoms, the team discovers that the patient has been hiding dark and dishonest secrets about his personal and professional life. But when the patient openly confesses his wrongdoings to his family and community, he compromises his chances of receiving the proper medical treatment. Meanwhile, House will stop at nothing to manipulate Taub into taking a DNA test to prove he is the father of his two six-month-old daughters.

A teenage boy attempting to follow in his late father’s footsteps as an entertainer is admitted to Princeton Plainsboro with partial paralysis. As the team searches for a bone marrow match, they uncover a disturbing family secret. Meanwhile, House looks for creative ways to remove his ankle monitor so that he can attend a boxing match in Atlantic City, and he treats a patient who is convinced he is suffering from diabetes. Also, Taub faces a tough decision when his ex-wife Rachel tells him that she wants to move across the country with their infant daughter.

The team learns that their 14-year-old patient is suffering from more than teen angst when her physical symptoms worsen. Despite Foreman’s firm opposition, House becomes obsessed with solving a peculiar case of a deceased four-year-old patient, which gets him into serious trouble. Meanwhile, Park tries to get Chase (Jesse Spencer) to admit the reason behind his recent obsession with grooming.

A prosecutor suffers from what he believes to be cardiac arrest during an interrogation at the witness stand. The team's preliminary diagnosis is hyper-anxiety, but when Adams and Park investigate the patient's home and find a hidden arsenal of firearms, they uncover a more alarming and deep-seated psychological disorder.

House and his team treat an Alzheimer's patient who vomits blood and flies into violent rages. Meanwhile, when Wilson tells House about a patient who has never had sex with her husband of 10 years, claiming A-sexuality, House makes a wager with him that there has to be an underlying cause.

When a runaway teen requires hospitalization, Adams butts heads with House when she insists they contact Social Services. Meanwhile, Taub has trouble forming a personal connection with his baby daughters and Foreman's relationship with a married woman comes out.

House and his team are placed under review after a staff member gets hurt.

Chase's religious faith bubbles to the surface when he treats a young nun. In addition, he and House reach a fundamental disagreement about the patient that may finally end Chase's reputation as House's "yes man" but also bring's House's methods, reputation and objectivity are given more serious scrutiny.

House's green-card wife, Dominika, will return in order to prove to the proper authorities that she and House are actually married. This in turn will lead to a crash course in which both will learn a little something about love and marriage.

House and the team battle to save a successful, independent blind man who is struck down by a mysterious illness, just prior to him asking for his girlfriend's hand in marriage. Meanwhile, House's mother unexpectedly arrives at Princeton Plainsboro to inform him of her new beau.

The team treats an Army veteran charged with treason after he leaked classified information. But the patient's life is put at risk when he refuses treatment unless he and his brother are given information about their late father, a war veteran, which raises questions about loyalty to one's family and country. Meanwhile, Adams suspects House may be sick, so she recruits Wilson and the other team members to plan an intervention and investigate his illness.

House and the team take on the case of a 22-year-old minor league hockey player who collapsed while coughing up blood after a fight on the ice. Meanwhile, House drops a bomb on Wilson, and Chase offers to help Park change her living arrangement.

House and the team take on the case of a man who starts tearing blood. Meanwhile, House is interviewing for a new favorite hooker, since his current favorite, Emily, has decided to get married and leave the business. Desperate for Emily "companionship," House teams up with his "wife" Dominika to sabotage Emily's budding relationship.

House and the team take on the case of a young boy who has violent dreams of being choked, and then wakes up but still can't take in air. Meanwhile, Park is having intimate dreams involving co-workers, which causes the team to question whether or not there's significance to what each of them dreams. Dominika discovers House has been keeping a secret from her and Wilson drops a bombshell on him.

When House and Wilson disappear off the grid for several days, without explanation, the team is left to deal with a complicated case of a 6-year old with numerous problems and complications, including an overbearing mother who also happens to be her physician.

Over the years, during the course of performing autopsies at Princeton-Plainsboro, Dr. Peter Treiber has often identified mistakes made by physicians that caused the patient's death. These observations have left him questioning the skills of nearly all the doctors on staff... all, that is, except House. When he falls ill, he demands that only House make medical decisions concerning his care. Unfortunately, House and Wilson have taken off on an impromptu road trip without telling anyone, leaving the team to fend alone and lie to their patient to make him believe that House is the guy calling all the shots.

The team takes on the case of Derrick, a 19-year-old college student who had a mysterious nose bleed during cheerleading practice, and discovers that his health issues are likely both physiological and psychological. Possibly suffering from schizophrenia, Derrick claims to hear his deceased brother’s voice in his head. Meanwhile, Foreman tries a different approach with House.

Facing a 6-month jail term, and the realization that he won't be there for Wilson at the end, House finds himself examining his entire life while contemplating a dismal future without his best friend.