Ten years after tracking down serial killer Jame Gumb, FBI Special Agent Clarice Starling (Moore) is unjustly blamed for a bungled drug raid. Starling and her connection to Hannibal Lecter (Hopkins) come to the attention of Lecter's only surviving victim, Mason Verger (Gary Oldman), a wealthy child molester whom Lecter left paralyzed and horribly disfigured during a therapy session.
Clarice Starling (Jodie Foster) is pulled from her training at the FBI Academy at Quantico, Virginia by Jack Crawford (Scott Glenn) of the Bureau's Behavioral Science Unit. He assigns her to interview Hannibal Lecter, a former psychiatrist and incarcerated cannibalistic serial killer, whose insight might prove useful in the pursuit of a serial killer nicknamed "Buffalo Bill", who skins his female victims' corpses.
In Baltimore, Maryland psychiatrist Dr. Hannibal Lecter attends a symphonic orchestra performance of A Midsummer Night's Dream. The flute player repeatedly misses out on his part, profoundly irritating Lecter. Later, Lecter hosts a dinner party in his townhouse for the orchestra's board of directors at which the disappearance of a musician, a flute player, is brought up during conversation.
In 1941, an eight-year-old Hannibal Lecter lives in Lecter Castle in Lithuania. Hitler's invasion of the Soviet Union turns the Baltic region into part of the bloodiest front line of World War II. Lecter, his younger sister Mischa, and their parents travel to the family's hunting lodge in the woods to elude the advancing German troops. After three years, the Nazis are finally driven out of the countries soon to be occupied by the Soviet Union. During their retreat, however, they destroy a Soviet tank that had stopped at the Lecter family's lodge looking for water. The explosion kills everyone but Lecter and Mischa. They survive in the cottage until six former Lithuanian militiamen, led by a Nazi collaborator named Vladis Grutas, storm and loot it. Finding no other food in the bitterly cold Baltic winter, the men look menacingly at Lecter and Mischa.
Will Graham (William Petersen) is a former FBI criminal profiler who has retired because of a mental breakdown after being attacked by a cannibalistic serial killer, Dr. Hannibal Lecktor (Brian Cox) whom he captured. Graham is approached at his Florida home by his former FBI superior Jack Crawford (Dennis Farina), who is seeking help with a new serial killer case. Promising his wife (Kim Greist) that he will do nothing more than examine evidence and not risk physical harm, Graham agrees to visit the most recent crime scene in Atlanta, where he tries to enter the mindset of the killer, now dubbed the "Tooth Fairy" by the police for the bite-marks left on his victims.