Frank Cotton, a twenty-nine-year-old pleasure-seeker, spends hours solving an intricate puzzle box created by Lemarchand, a French maker of singing birds. Frank purchased the box from a man called Kircher, who promised it would open a doorway to extraordinary pleasure. As Frank completes the puzzle, a great bell tolls from beyond the visible world, and the east wall loses solidity, revealing a dark, chaotic realm. Four figures emerge: the Cenobites, members of an otherworldly order devoted to extreme sensation. Their flesh is grotesquely disfigured and transfixed with hooks and chains. Frank asks for pleasure, and the Cenobites warn there is no going back. He insists. His senses are amplified to agonizing extremes, and memories flood him uncontrollably. When the torment subsides, the fourth Cenobite reveals herself atop a pile of rotting human heads. Frank realizes there is no pleasure here as humankind understands it. The Cenobite announces the real ordeal is about to begin.
The narrative shifts forward. Rory, Frank's brother, and his wife Julia move into the house on Lodovico Street, willed jointly to the brothers after their grandmother's death. On moving day, Kirsty, a young woman quietly infatuated with Rory, arrives to help. While exploring upstairs, Julia enters the largest room and finds its blinds nailed shut. The room is cold and oppressive, and the door slams shut on its own. She locks it and insists they use a smaller bedroom. The locked room becomes known as the damp room.
Julia's past with Frank surfaces through memory. A fortnight before her wedding to Rory, Frank appeared, tanned and charming. Julia succumbed within hours. Their coupling was aggressive and joyless. Frank disappeared the next day, and Julia has secretly mourned him since, thinking of him while making love to Rory. In the present, she begins visiting the damp room alone, sitting in its darkness. One Saturday, Rory cuts his thumb deeply and rushes upstairs, dripping blood onto the damp room's bare boards. The next day, the bloodstains have vanished.
During a housewarming party, Julia slips upstairs to the damp room. In the darkness, she hears scratching. The wall glows and appears to come apart, revealing a figure: a ruin of a human being, ripped apart and reassembled with most pieces missing. Despite its catastrophic state, it lives. The figure speaks her name, identifies itself as Frank, and asks for blood. Julia deduces that Frank's remnant fed on Rory's spilled blood and gained enough strength to make contact. She resolves to supply more, believing that if she restores Frank, he will be hers.
Frank's perspective reveals his backstory. After leaving Julia, he traveled east, but everything slipped through his fingers, and he spiraled into depression and opiate addiction. He heard rumors of Lemarchand's box, a device said to open a doorway to new pleasures, and tracked down Kircher in Düsseldorf. From his otherworldly prison, Frank can see into the room where he solved the puzzle. He knows that if a prisoner escapes back into the room, the Cenobites cannot follow without being summoned. His last act before capture was to leave a trace of himself on the floor. When Rory bled on those boards, Frank gained a fingerhold on reality.
Julia begins killing to feed Frank. She lures a man from a bar to the damp room and stabs him. The blood crawls across the floor toward Frank's hiding place, and the corpse is drained to a withered husk. Frank speaks from the shadows, half-made and refusing to be seen, demanding more blood. Julia kills again, and Frank grows dramatically: Muscle ripens over raw cartilage, and his voice becomes recognizably his own. He warns Julia he must become whole quickly.
Kirsty, sent by the worried Rory to check on Julia, visits the house and notices a man's raincoat on the hall stand. Julia turns hostile and slams the door. Kirsty concludes Julia has a lover. The next day, she stakes out the house and watches Julia return with a man. Inside, the man resists, and Frank, now inhumanly strong, seizes him. Kirsty enters through the unlocked back door and witnesses the bandaged creature crushing its victim until blood spurts from his face.
Frank grabs Kirsty and hauls her into the damp room, identifying himself as Rory's brother. She fights back, gouging his face and tearing away bandages. She picks up a box from the floor and strikes him. When she raises it again, Frank freezes, fixated on the box with unmistakable fear. She throws it through the window, and while Frank screams, she escapes with the box and collapses on a nearby street.
In her hospital room, Kirsty examines the box and inadvertently works its puzzle. A Cenobite materializes and explains that the box, called the Lemarchand Configuration, is a means of summoning their order. Kirsty must accompany it. Desperate, she bargains: She will deliver Frank instead. The Cenobite agrees, on the condition that Kirsty make Frank confess his identity.
Kirsty walks to Lodovico Street. Inside the house, Rory sits at the dining table with dried blood on his face. He tells Kirsty that Frank is dead and invites her upstairs to see the body: a skinless corpse in torn bandaging. Kirsty retreats, panicked, believing the Cenobites will claim her since Frank is apparently dead. As she reaches the hallway, the figure she has taken for Rory opens his arms and says, "Come to Daddy" (146). The words trigger recognition: Frank used the same phrase when he attacked her. She realizes that Frank has killed Rory, stolen his skin, and grafted it onto his own body. The skinless corpse upstairs is Rory. She rakes the impostor's cheek, and the grafted skin slides away, revealing raw flesh.
The house erupts in supernatural chaos. Frank pursues Kirsty with a knife. Julia seizes Kirsty from behind, but Kirsty wrenches Julia into Frank's path, and his knife buries itself in Julia's side. Frank draws Julia close and feeds on her. Kirsty flees upstairs and is cornered in Frank's room, where she falls onto Rory's corpse in the dark. Remembering the Cenobite's condition, she presses Frank to identify himself. He finally declares, "I'm Frank" (157).
The Cenobites materialize and order Kirsty to leave. Hooks sink into Frank's flesh, chains holding him taut. In a final act of defiance, he meets Kirsty's gaze and flicks his tongue across his teeth. Then his body comes apart: Limbs separate from torso, head from shoulders.
Kirsty staggers downstairs. In the dining room, she finds Julia in her wedding dress and veil, but the voice comes from Julia's severed head resting in the bride's lap. The veil rises to reveal blazing light, and a voice announces itself as the Engineer, the fifth figure whose arrival was deferred when Frank first summoned the Cenobites. Kirsty flees as the house collapses around her.
Outside, the Engineer presses the resealed box back into Kirsty's hand. She glimpses Frank's and Julia's faces in the lacquer, but not Rory's. She speculates that Rory may be accessible through other puzzles and resolves to wait and watch, as she has always done.