Roy G. Basch is a new intern in internal medicine at a hospital called the House of God. He begins his internship under the tutelage of the Fat Man, a second year resident who has some crazy ideas as to how to take care of patients. According to the Fat Man, there are two types of patients: the dying young and gomers. Gomers are elderly, demented patients from outside nursing homes who barely qualify as being human and who, the Fat Man says, never die. Only the young are sick enough to die at the House of God.

Roy starts his internship fairly scared. He meets his fellow interns, Potts, Hyper Hooper, Chuck, Eat My Dust Eddy and the Runt—all scared and new to internship and patient care. Roy gets assigned duty with Chuck and Potts under the Fat Man on an internal medicine ward. Each takes turns being on call, and he is third in line the first week. Before being on call, he learns of several of the Fat Man's rules like "Gomers never die" and "Gomers go to ground". He learns about the hierarchy of the House of God—from private doctors down to the lowly intern. He learns about "buffing" charts so they make the patient and the doctor look good and about "turfing" patients—sending them to other places based on trumped up reasons why they should be turfed to another facility or ward. The first three weeks are hard but he learns a lot from the Fat Man and begins to cope.

Three weeks into his internship, the chain of command changes. Roy begins to work under the overzealous Jo, a second year resident who believes in doing as much as possible to everyone. Roy tries to do this and realizes that, just like the Fat Man said, it made many of the gomers worse. This is when he decides to fake everything, do nothing to the gomers and to simply buff the chart saying he did a lot of things he never did. The gomers actually get better, and Roy is given praise by he higher ups. Unfortunately, he's also given the distinction of being able to handle the "toughies" which makes his load a lot greater. His shift changes slightly, and he works with the Runt and Chuck. He admits Saul, the leukemic patient, and brings him into remission. He and his friends develop sexual relationships with the female staff with Roy sleeping not only with his girlfriend but with Molly, the nurse. Potts sleeps with a nurse, and both Roy and the Runt sleep with Social Services staff in order to get better placement for their gomers.

Eventually, he gets transferred to the Emergency Ward, where he learns to Buff and Turf patients and spends his time talking with Gilheeny and Quick, two policemen who hang out there. He works with two surgical residents and meets Abe, the guy who lives in the waiting room of the hospital. He takes care of overdoses, cardiac cases and some surgical cases on an every other night rotation. Abe disappears for awhile and then returns, getting paranoid and out of sorts. Abe eventually ends up in the state hospital. Gilheeny gets shot but survives. Roy survives this rotation.

Roy then ends up with the Fat Man on ward 4 North, considered the worst ward of them all.. He deals with death and more gomers that are more difficult to get rid of. Everyone starts to lose it, and several patients die due to malpractice. Eat My Dust Eddie becomes mentally unbalanced and is taken off the ward. Potts is faced with the death of the Yellow Man, whose sickness he was responsible for. He commits suicide by jumping from an eighth story window of the hospital. Berry is worried about Roy who is seeming increasingly imbalanced. Roy does the unthinkable and purposely kills a patient so he won't suffer.

By April, Roy is transferred to the MICU where most of the patients are on ventilators. He's afraid of dealing with these patients, at first. He meets Pinkus, a cardiologist whose answer to death is to run and have a hobby. Roy is afraid he's going to die when he runs into a patient on the Unit that was one of the Best Medical Students at the hospital. The BMS got a cold and now is in multiple organ failure. The BMS dies, and Roy takes up running as a way to cope with his own possible death.

After dealing with multiple deaths in the Unit, Jo cracks, and Roy is nonplussed. He continues running and watches Pinkus in a marathon. He's transferred out of the unit but doesn't want to go. He's finally manhandled by other interns and his policeman friends and forced to go to a mime show. He finally breaks down and tells Berry everything—including the fact that he killed Saul. With Berry's help, he begins the healing process.

Next, it is time to decide whether or not to go on in medicine and do two years of the residency. Roy doesn't want to and wants to take the year off. The Fats has a colloquium to discuss the various options the interns have, and they all decide on psychiatry. This inflames the higher ups who talk to each intern about their decision. The interns are angry at the higher ups and blame them for Potts death and for not being role models for the interns to look up to.

Potts finally reaches the end of his residency and is much wiser. The says goodbye to the people he cares about and makes the decision to go into psychiatry after taking a year off. He and Berry go on a long vacation to the South of France.