In 1990, Clarice Starling is pulled from her FBI training at the Quantico, Virginia FBI Academy by Jack Crawford of the Bureau's Behavioral Science Unit. He assigns her to interview Hannibal Lecter, a former psychiatrist and incarcerated cannibalistic serial killer. Crawford believes Lecter's insight could prove useful in the pursuit of a psychopath serial killer nicknamed "Buffalo Bill", who kills young women and removes their skin from their bodies.
At the Baltimore State Hospital for the Criminally Insane, Dr. Frederick Chilton makes a crude pass at Starling before he escorts her to Lecter's cell. Although initially pleasant and courteous, Lecter grows impatient with Starling's interviewing and rebuffs her. As she is leaving, a prisoner named Miggs flicks semen at her. Lecter, who considers this an "unspeakably ugly" act, calls Starling back and tells her to seek out his old patient. This leads her to a storage facility, where she discovers a jar containing a man's severed head. She returns to Lecter, who says the man is linked to Buffalo Bill. He offers to profile Buffalo Bill on condition he be transferred away from Chilton, whom he detests. Another Buffalo Bill victim is found with a death's head moth lodged in her throat.
Buffalo Bill abducts Catherine Martin, the daughter of a United States senator. Crawford authorizes Starling to offer Lecter a fake deal, promising a prison transfer if he provides information that helps them capture Buffalo Bill and rescue Catherine. Instead, Lecter demands a quid pro quo from Starling, offering clues about Buffalo Bill in exchange for personal information. Starling tells Lecter about her father's murder when she was ten years old. Chilton secretly records the conversation and reveals Starling's deceit to Lecter before offering him a different deal. Lecter agrees and is flown to Memphis, where he meets and torments Senator Martin, then gives her false information on Buffalo Bill, including that his name is "Louis Friend".
Starling figures out that "Louis Friend" is an anagram of "iron sulfide"—fool's gold. She visits Lecter, who is now imprisoned in a cell in a Tennessee courthouse, and requests the truth. Lecter says all the information she needs is contained in the Buffalo Bill case file, then insists on continuing their quid pro quo. She recounts a traumatic childhood incident of hearing spring lambs being slaughtered on a relative's Montana farm. Lecter speculates that Starling hopes that saving Catherine will end the recurring nightmares she has of lambs screaming. Lecter returns the Buffalo Bill case files to Starling as Chilton arrives and has the police escort her from the building. Later that evening, Lecter kills his guards (one of them is graphically disemboweled), escapes from his cell, and disappears.
Starling analyzes Lecter's file annotations and figures out that Buffalo Bill knew his first victim, Frederika Bimmel. Starling travels to her Ohio hometown and discovers both she and Buffalo Bill were tailors. At Frederika's home, she notices unfinished dresses and dress patterns identical to the patches of skin removed from the victims. She phones Crawford and says Buffalo Bill is making a "suit" with human skin. 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. Gumb smuggled death's head moths into the U.S. and was refused a sex-change operation, mistakenly believing he was transsexual. Starling continues interviewing Frederika's friends while Crawford and an FBI HRT storm Gumb's address in Illinois, finding the house empty. Meanwhile, Starling goes to interview another person who knew Frederika. At the house, she meets "Jack Gordon", but realizes he is Gumb after spotting a death's head moth flying loose. She pursues him into a cavernous basement and finds Catherine trapped in a dry well. In a dark room, Gumb stalks Starling with night-vision goggles, but reveals himself by cocking his revolver. Starling reacts quickly and shoots Gumb dead.
At the FBI Academy graduation party, Starling receives a phone call from Lecter, who is at a Bimini airport. He assures her that he has no intention of pursuing her and requests that she return the favor, which she says she cannot. Lecter subsequently hangs up the phone because he is "having an old friend for dinner." He trails a newly arrived Chilton into the crowd.
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