A decade after tracking down serial killer Jame Gumb, FBI Special Agent Clarice Starling is blamed for a botched drug raid which results in the deaths of five people. Starling is contacted by Mason Verger, the only surviving victim of the cannibalistic serial killer Hannibal Lecter, who has been missing since escaping custody during the Gumb investigation. A wealthy child molester, Verger was paralyzed and disfigured by Lecter during a therapy session. He has been pursuing an elaborate scheme to capture, torture, and kill Lecter ever since. Using his wealth and political influence, Verger has Starling reassigned to Lecter's case, hoping her involvement will draw Lecter out.
After learning of Starling's disgrace, Lecter sends her a taunting letter. A perfume expert identifies a fragrance on the letter: skin cream with ingredients only available to a few shops in the world. She contacts the police departments of the cities where the shops are located, requesting surveillance tapes. In Florence, Chief Inspector Rinaldo Pazzi is investigating the disappearance of a library curator. Pazzi questions Lecter, who is masquerading as Dr. Fell, the assistant curator and caretaker.
Recognizing Dr. Fell in the surveillance tape, Pazzi accesses the Violent Criminal Apprehension Program database of wanted fugitives. He learns of Verger's US$3 million personal bounty on Lecter. Seeking the bounty, Pazzi ignores Starling's warnings and attempts to capture Lecter alone. He recruits a pickpocket to obtain Lecter's fingerprint to show Verger as proof. The pickpocket manages to get the print and gives it to Pazzi, but is fatally wounded in the process when Lecter severs his femoral artery. Lecter baits Pazzi into an isolated room of the Palazzo Vecchio, ties him up, disembowels him, and hangs him from the balcony.
Verger bribes Justice Department official Paul Krendler to accuse Starling of withholding a note from Lecter, leading to her suspension. Lecter lures Starling to Union Station. Verger's men, having trailed Starling, capture and bring Lecter to Verger. Verger intends to feed Lecter alive to a herd of wild boars bred for this purpose. After her superiors refuse to act, Starling infiltrates Verger's estate. After neutralizing two guards and freeing Lecter, she is shot by a third guard. Lecter picks up an unconscious Starling just before the boars break through the doors, devouring the two guards but ignoring Lecter. Verger orders his physician Cordell Doemling to shoot Lecter. At Lecter's suggestion, Cordell shoves his hated boss into the pen with Lecter offering to take the blame. Lecter carries Starling away while Verger is eaten alive by his own boars.
Lecter takes Starling to Krendler's secluded lake house and treats her wound. When Krendler arrives, Lecter subdues and drugs him. Starling, disoriented by morphine and dressed in a cocktail dress, awakens to find Krendler seated at the table set for an elegant dinner. Weakened by the drugs, she watches in horror as Lecter opens Krendler's skull, removes part of his prefrontal cortex, sautés it, and feeds it to him. Starling tries to attack Lecter with a butter knife, but he overpowers and traps her. She handcuffs his wrist to hers. Hearing the police closing in, Lecter is about to sever her cuffed hand to escape and brings down the cleaver. Starling surrenders to the FBI with her hands intact.
On a flight, Lecter, who is now one-handed, prepares to eat a meal he has brought himself, while wearing his bandaged arm in a sling. Lecter shares Krendler's cooked brain with a curious boy who was watching him eat, saying it is important "always to try new things". As the unsuspecting boy eats, Lecter looks on with an expression of restrained delight.
Anthony Hopkins as Dr. Hannibal Lecter / Dr. Fell
Julianne Moore as FBI Agent Clarice Starling
Gary Oldman as Mason Verger[b]
Ray Liotta as Paul Krendler
Frankie R. Faison as Barney Matthews
Giancarlo Giannini as Chief Inspector Rinaldo Pazzi
Francesca Neri as Allegra Pazzi
Željko Ivanek as Dr. Cordell Doemling
David Andrews as FBI Agent Clint Pearsall
Francis Guinan as FBI Assistant Director Noonan
Robert Rietti as Sogliato
Enrico Lo Verso as Gnocco
Ivano Marescotti as Carlo Deogracias
Fabrizio Gifuni as Fabrizio
Marco Greco as Tommaso
Hazelle Goodman as Evelda Drumgo
Terry Serpico as Officer Bolton
Boyd Kestner as FBI Agent Burke
Peter Shaw as FBI Agent John Brigham
James Opher as DEA Agent Eldridge
Don McManus as Benny Holcombe
Danielle de Niese as Beatrice in Vide Cor Meum
Mark Margolis and Ajay Naidu as Perfume Experts
based on the 1999 novel by Thomas Harris
sequel to the 1991 film The Silence of the Lambs