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The story, narrated by the gigantic but docile half-Native American inmate "Chief" Bromden, focuses on the antics of the rebellious Randle Patrick McMurphy, who faked insanity to serve out his prison sentence for statutory rape in the hospital. The head administrative nurse, Mildred Ratched, rules the ward with a mailed fist and with little medical oversight. She is assisted by her three black day-shift orderlies, and her assistant doctors.
McMurphy constantly antagonizes Nurse Ratched and upsets the routines, leading to constant power struggles between the inmate and the nurse. He runs a card table, captains the ward's basketball team, comments on Nurse Ratched's figure, incites the other patients on the ward to conduct a vote on watching the World Series on television, and organizes an unsupervised deep sea fishing trip. His reaction after failing to lift a heavy shower room control panel (which he had claimed to be able to) – "But at least I tried." – gives the men incentive to try to stand up for themselves, to do their best instead of allowing Nurse Ratched to take control of everything they do. The Chief opens up to McMurphy and reveals late one night that he can speak and hear. A disturbance after the fishing trip results in McMurphy and the Chief being sent for electroshock therapy sessions, but even this experience does little to tamp down McMurphy's rambunctious behavior.
One night, after bribing the night orderly, McMurphy breaks into the pharmacy and smuggles bottles of liquor and two prostitute girlfriends onto the ward. McMurphy persuades one of the women to seduce Billy Bibbit, a timid, boyish patient, with a terrible stutter and little experience with women, so that he can lose his virginity. Although McMurphy plans to escape before the morning shift arrives, he and the other patients fall asleep instead without cleaning up the mess and the staff finds the ward in complete disarray. Nurse Ratched finds Billy and the prostitute in each other's arms, partially dressed, and admonishes him. Billy asserts himself for the first time, answering Nurse Ratched without stuttering. Ratched calmly threatens to tell Billy's mother what she has seen. Billy has an emotional breakdown and, once left alone in the doctor's office, commits suicide by cutting his throat. Nurse Ratched blames McMurphy for the loss of Billy's life. Enraged at what she has done to Billy, McMurphy attacks her and attempts to strangle her to death and tears off her uniform, revealing her breasts to the patients and aides watching. He has to be dragged away from her and is moved to the Disturbed ward.
Nurse Ratched misses a week of work due to her injuries, during which time many of the patients either transfer to other wards or check out of the hospital forever. When she returns, she cannot speak and is thus deprived of her most potent tool to keep the men in line. Most of the patients leave shortly after this event. Later, after Bromden, Martini, and Scanlon are the only original patients left on the ward, McMurphy is brought back in. He has received a lobotomy and is now in a vegetative state, silent and motionless. The Chief later smothers McMurphy with a pillow during the night in an act of mercy, before throwing the shower room control panel, the same one McMurphy could not lift earlier, through a window, and escaping the hospital.
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