Following his murderous quest for vengeance in the previous film, Dr. Anton Phibes eludes capture by placing himself in suspended animation in a sarcophagus shared with his wife's body. He plans to return when the Moon enters into a specific alignment with the planets not seen in 2,000 years. Three years later, the conjunction occurs and Phibes rises from his sarcophagus. Summoning his silent assistant Vulnavia (Valli Kemp, replacing Virginia North), Phibes prepares to take Victoria's body to Egypt; there, in a hidden temple, flows the River of Life, promising resurrection for Victoria and eternal life for them both. Emerging from his basement, Phibes discovers that his mansion has been demolished. A safe, containing an ancient papyrus map to the river, is now empty.
Phibes knows of only one person who could be seeking the same goal: Darius Biederbeck (Robert Quarry), a man who has lived for centuries through the regular use of a special elixir. After translating the papyrus, Biederbeck prepares to travel to Egypt to find the River of Life for himself and his lover Diana (Fiona Lewis). Phibes and Vulnavia enter Biederbeck's house, kill his manservant, and reclaim the papyrus; they leave for Southampton to take a ship to Egypt. Biederbeck follows and travels on the same ship with Diana and his assistant Ambrose (Hugh Griffith). When Ambrose discovers Victoria's body stored in the hold, Phibes kills him. His body is stuffed in a giant bottle and thrown overboard. Inspector Trout (Peter Jeffrey) discovers the corpse when the bottle washes ashore near Southampton. He and Superintendent Waverley (John Cater) question shipping agent Lombardo (Terry-Thomas); upon hearing the descriptions of the tall woman (Vulnavia) and a clockwork band being loaded aboard, they realize that Dr. Phibes has somehow returned.
Trout and Waverley pursue Phibes to Egypt, catching up to Biederbeck's archaeological party near the mountain housing the hidden temple. Phibes, having set up residence inside the temple, hides Victoria's body in a secret compartment of an empty sarcophagus. He also finds the silver key that opens the gates to the River of Life. Phibes kills each of Biederbeck's men using methods inspired by Egyptian mythology: one man is killed by a hawk, another is stung to death by scorpions. Biederbeck's team eventually breaks into the temple and takes the sarcophagus, and Biederbeck discovers the key. Using a giant fan to simulate a windstorm, Vulnavia enters the tent with the sarcophagus and Phibes uses a giant screw press to crush the man guarding it. Though the sarcophagus is retrieved and Victoria's body is safe, Phibes discovers that the key is missing.
Biederbeck is unmoved by the murders and insists on continuing. He sends Diana and Hackett (Gerald Sim), the last remaining team member, back to England. Hackett leaves his truck to contact a unit of British troops, but finds they are really more of Phibes' clockwork men. When he returns to the truck, Diana is gone and he is sand-blasted to death. His truck crashes into Biederbeck's tent.
Realizing Phibes must have taken Diana, Biederbeck confronts him. Phibes demands the key in exchange for Diana's life, claiming that thanks to the ancient builders of the temple, when the gate is opened the water will drain out of Diana's trap and flow through the gate thus making it possible to free her without injury. Unable to free her from Phibes' water trap, Biederbeck surrenders the key and gives up his quest. Phibes unlocks the gate to the River of Life, boats Victoria's coffin through it, and summons Vulnavia to join them on the other side.
Biederbeck returns to the gate just as it closes, pleading through the bars for Phibes to take him along, but Phibes ignores him and poles the boat down the ancient passageway. Diana attempts to comfort Biederbeck, but he begins to rapidly age. The boat slowly fades from sight. Phibes is heard singing "Over the Rainbow" as Biederbeck finally succumbs to extreme old age.
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