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Clarice Starling (Foster) is pulled from her training at the FBI Academy at Quantico, Virginia, by Jack Crawford (Glenn) of the Bureau's Behavioral Science Unit. He tasks her with interviewing Hannibal Lecter (Hopkins), a former psychiatrist and incarcerated cannibalistic serial killer, believing Lecter's insight might be useful in the pursuit of a serial killer nicknamed "Buffalo Bill" (Levine), who skins his female victims' corpses.
Starling travels to the Baltimore State Hospital for the Criminally Insane, where she is led by Dr. Frederick Chilton (Anthony Heald) to Lecter's solitary quarters. Although initially pleasant and courteous, Lecter grows impatient with Starling's attempts at "dissecting" him and rebuffs her. As she is leaving, one of the prisoners flicks semen at her. Lecter, who considers the discourtesy "unspeakably ugly", calls Starling back and tells her to seek out an old patient of his. This leads her to a storage shed where she discovers a man's severed head. She returns to Lecter, who tells her that the man is linked to Buffalo Bill. He offers to profile Buffalo Bill on the condition that he be transferred away from Chilton, whom he detests.
When Buffalo Bill kidnaps a U.S. senator's daughter, Catherine Martin, Crawford authorizes Starling to offer Lecter a fake deal promising a prison transfer if he provides information that helps find Buffalo Bill and rescue the abductee. Instead, Lecter begins a game of quid pro quo with Starling, offering comprehensive clues and insights about Buffalo Bill if Starling will give him information about her own past, something she was advised not to do. Chilton secretly records the conversation and reveals Starling's deal as a sham before offering to transfer Lecter in exchange for a deal of Chilton's own making. Lecter agrees and is flown to Memphis, where he reveals personal information on Buffalo Bill to federal agents.
As the manhunt begins, Starling visits Lecter at his special cell in a Tennessee courthouse and confronts him with her decryption of the name he provided ("Louis Friend", an anagram of "iron sulfide", also known as fool's gold). Lecter refuses Starling's pleas for the truth, and forces her to recount her traumatic childhood. She tells him how she was orphaned and relocated to a relative's farm, where she discovered a lamb slaughterhouse and made a failed attempt to rescue one of the lambs. Lecter gives her the case files on Buffalo Bill after their conversation is interrupted by Chilton and the police who escort her from the building. Later that evening, Lecter kills his two guards, escapes from his cell, and disappears.
Starling analyzes Lecter's annotations to the case files and realizes that Buffalo Bill knew his first victim personally. Starling travels to the victim's hometown and discovers that Buffalo Bill was a tailor, with dresses and dress patterns identical to the patches of skin removed from each of his victims. She telephones Crawford to inform him that Buffalo Bill is trying to fashion a "woman suit" of real skin, but Crawford is already en route to make an arrest, having cross-referenced Lecter's notes with hospital archives and finding a man named Jame Gumb, who once applied unsuccessfully for a sex-change operation. Starling continues interviewing friends of Buffalo Bill's first victim while Crawford leads an FBI tactical team to Gumb's address in Illinois. Starling is led to the house of "Jack Gordon", who she realizes is actually Jame Gumb. She pursues him into his multi-room basement, where she discovers that Catherine is still alive, but trapped in a dry well. After turning off the basement lights, Gumb stalks Starling in the dark with night-vision goggles but gives his position away when he cocks his revolver; Starling turns around just in time and kills him.
Some time later at her FBI Academy graduation party, Starling receives a phone call from Lecter, who is at an airport in Bimini. He assures her that he does not plan to pursue her and asks her to return the favor, which she says she cannot do. Lecter then hangs up the phone, saying that he is "having an old friend for dinner", and begins following a newly arrived Chilton before disappearing into the crowd.