Simone and Eddie (Tanedra Howard and Marty Moreau), two predatory lenders, awaken in a room with a caged-in scale in the center, wearing head harnesses. Screws are poised to drill into their skulls; the person who cuts off more flesh weight in sixty seconds will live, while the other will be killed by the screws. The overweight Eddie cuts fat from his body, but Simone chops her left arm off and tips the scale in her favor, saving herself. Lieutenant Mark Hoffman (Costas Mandylor) is called to the scene by Dan Erickson (Mark Rolston), who found Peter Strahm's fingerprints around the room. Erickson also reveals that Lindsey Perez (Athena Karkanis) is alive; he explains that he protected Perez after her incident in Saw IV due to her being a target of an unknown accomplice, now believed to be Strahm. Hoffman is called to the hospital to question Simone; while there, he is pestered by Pamela Jenkins (Samantha Lemole), a journalist, about the death of John Kramer (Tobin Bell).
William Easton (Peter Outerbridge), a health insurance executive, talks with his company's attorney about Harold Abbott (George Newbern), whose insurance policy was revoked after a discrepancy was found on his application and who later died from his illness. At the morgue during Eddie's autopsy, Hoffman is shown by Dr. Heffner (James Van Patten), who had performed the autopsies for all of Jigsaw's victims, that the person who cut the jigsaw piece from Eddie's skin used a knife used on only one other victim: Seth Baxter. Jill Tuck (Betsy Russell) meets with Hoffman at her clinic; he informs her that he is taking control of the games, and Jill hands him five envelopes received in the box from John's will, keeping the sixth to herself. It is revealed that in this same room, she once spoke with John about his ways of rehabilitation; he brought Amanda Young (Shawnee Smith), who Jill had once deemed a "lost cause", to her as proof that his ways could really work.
In his office, William is kidnapped and placed in a trap. A large vise encloses his torso, his wrists bound and a breathing mask covering his face. Hank (Gerry Mendicino), his janitor and a smoker, is in the same situation across from him. A videotape of John himself informs William that in sixty minutes, the four bombs strapped to his limbs will detonate, dismembering him. For the first test, if either man breathes, the vise will close around his torso; Hank is killed when he fails to hold his breath for long. As William removes the first explosive, it is revealed that he and John first met at the opening of Jill's clinic, and that John immediately found fault in William's policies, which essentially decided the probabilities of who lived and who died. In the second test, Jigsaw's puppet informs William that he must choose to save either his file clerk or secretary, named Allen and Addy (Shawn Ahmed and Janelle Hutchison) respectively, and let the other die; they stand side by side on retractable platforms with nooses around their necks. Allen is young and in good health but has no family, while Addy is middle-aged and ill but is surrounded by family. In the end, William chooses to save Addy, and Allen is hanged when his platform retracts.
As Hoffman oversees the tests from an observation room, three more captives wake up in cages, each cage holding a tank of hydrofluoric acid. One cage holds Tara and Brent (Shauna MacDonald and Devon Bostick), a mother and son; the other cage holds Pamela. The former cage contains a switch labeled "Live" and "Die". Erickson calls and informs Hoffman that the tape for the Seth Baxter murder was found, and Hoffman leaves to meet with him. It is revealed that Hoffman abducted Timothy Young (Mpho Koaho) and placed him in the limb-breaking trap from Saw III. Mutual dislike stood between Hoffman and Amanda, as neither trusted the other to properly carry on John's work. Jill met with John at the plant soon after, and he gave her the key to the box from his will and the promise that when his work was finished, she would be protected from all suspicion.
As William continues to his third test, it is revealed that John met with him after being diagnosed with cancer to gain coverage for a treatment that might have cured him, but William turned him down. In a large boiler room, the company attorney, Debbie (Caroline Cave), stands at the bottom of a caged-in maze with a device on her chest set to fire a spear through her head. She has ninety seconds to find the key to this device, and William must help her by diverting jets of scalding hot steam from her path directly onto himself. At the end of the maze, Debbie discovers through X-ray films that the key has been implanted in William's side; she attacks him with a circular saw, but fails to strike him before the timer runs out and kills her. In the final test, William finds his six junior staff members chained to a spinning carousel. A shotgun is set to fire and kill all six of them at random, but William can choose to save two of the six by pushing buttons in a device that will drive spikes into his hand and divert the shotgun upward. He reluctantly chooses to save Emily and Shelby, and the other four are killed; with his tests finished, he removes the last bomb and moves on to find a way out.
Meanwhile, Erickson and Perez inform Hoffman that abnormalities were found in Strahm's fingerprints, and that the scrambled voice from the Seth Baxter tape did not match Jigsaw's. They lead a worried Hoffman to the site where the voice is being unscrambled by a technician, where they relentlessly question Hoffman about the inconsistencies in Strahm working with Jigsaw, including the fact that Strahm was dead when his prints were found. The moment Hoffman's voice is unscrambled from the tape, he attacks and kills all three of them, pulls out Strahm's severed hand (preserved in a box of ice) and plants Strahm's prints around the room, then sets it on fire to burn the bodies and evidence. At the same time, Jill enters the observation room monitoring the two cages, leaving a letter by the computers - the same paper that Pamela left with her earlier before being captured.
When Hoffman returns, he finds the letter, which he himself had written to Amanda: he had discovered that she had pushed Cecil Adams (Billy Otis) into robbing the clinic, making her responsible for Jill's miscarriage. Hoffman used this information to blackmail Amanda into killing Lynn Denlon, threatening to tell John otherwise. Jill enters suddenly and attacks him from behind, while William simultaneously reaches the end of his path, finding himself between the two cages. It is revealed that he and Pamela are brother and sister, while Tara and Brent are the family of Harold Abbott. The test is theirs, and they can choose to either kill William or set him free using the marked switch next to the tank. When Tara hesitates, Brent angrily shifts the switch to "Die", and a platform of needles swings into William's back, pumping the acid into his body and dissolving his torso as the three watch in horror. Jill straps Hoffman to the chair and places an updated "Reverse Bear-Trap" on his head: the sixth envelope was John's instructions to capture Hoffman, as he is now the only person alive aware of Jill's involvement. She leaves Hoffman with a forty-five second timer; he escapes the chair by breaking his hand with the trap's weight and freeing himself, then jams the trap into the door's frame to stop it from fully opening, screaming as he pulls his head free, his mouth partially ripped open.
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