A severely deformed man stumbles through the Arizona desert, falls, and dies. Dr. Matt Hastings, a doctor from the nearby town of Desert Rock, Arizona, is called in by the sheriff to examine the body. Asked the cause of death, he finds himself perplexed; the deceased, biological research scientist Eric Jacobs, was someone he knew and had recently seen. He appears to have acromegaly, a distortion that takes years to reach its current state. Puzzled, Dr. Hastings asks to perform an autopsy. The sheriff judges it unnecessary, since no indication of foul play was found. Hastings approaches Jacobs' colleague, Dr. Gerald Deemer, who bluntly refuses permission. He signs Jacobs' death certificate, with "heart disease" listed as the cause of death.
Still bothered, Hastings drives to Deemer's home and research laboratory in an isolated desert mansion. Deemer apologizes for his earlier hostility, blaming it on grief, and insists that Jacobs developed acromegaly rapidly, over just four days. He cannot offer an explanation, but attempts to convince Hastings this was an anomaly, not a result of anything sinister. Hastings appears to accept his apology.
Deemer goes to his closed lab, which contains huge cages with white rabbits and rats of enormous size. Deemer examines each, noting when each last received an "injection", and how many each has had. He turns to a glass-front inset in a back wall, as a different specimen crawls into view: a tarantula with a body the size of a large dog, plus its legs.
As Deemer finishes his observations, a second deformed man appears, attacks Deemer and begins destroying the lab. During the rampage, the lab catches fire and the glass covering the tarantula's cage is shattered. The man grabs the hypodermic needle that Deemer was preparing, knocks him out, and injects him with the contents. As flames engulf the lab, the arachnid escapes and the deformed man collapses and dies. Deemer regains consciousness, grabs a fire extinguisher and puts out the fire. That night, Deemer calmly buries the body of his other assistant, Paul Lund, in the desert.
The intercity bus brings a newcomer to town, a young, beautiful woman, who is expecting to be met by Dr. Deemer. Told by the hotel clerk that she will have to wait until the only taxi returns, she accepts a ride from Dr. Hastings, who is going back to Deemer's lab. She introduces herself as Stephanie Clayton, nicknamed "Steve", who has signed on to assist in the lab.
At the mansion, Dr. Deemer tells them that the fire was caused by an equipment malfunction. He indicates that all the test animals were killed and explains that Lund has already left his employment. Since Steve's contract stipulates that she live at the residence, Hastings leaves her and her suitcases there.
Days later, the sheriff calls and asks Dr. Hastings for help. Hastings finds a mystery involving picked-clean cattle carcasses and large pools of a thick, white liquid. The tarantula, now grown to huge proportions, is the cause. The next night, a horse rancher and two men inside a pickup truck are also killed.
Hastings pays a call on Steve at the lab. Dr. Deemer has been acting strangely and looking ill, and has gone to bed, so she shows Hastings what they are working on - the use of radioactive elements to produce an artificial super-nutrient which, once perfected, could provide an unlimited food supply for humanity. She shows Hastings some of the giant lab animals created as an unintended side effect. Dr. Deemer suddenly appears and is angry with Steve for revealing "secret" work and orders Hastings to leave.
At the destroyed horse ranch, Hastings looks round at the request of the sheriff, and once again finds pools of the strange, thick liquid. He decides an analysis could solve the mystery, so he takes samples and flies them to the Arizona Agricultural Institute in Phoenix. The substance is determined to be tarantula venom, but in such a quantity that only a monster arachnid could produce. After being shown a film demonstrating the predatory ferocity of a normal tarantula, he calls Dr. Deemer, but is told by Steve that he is sick in bed. Deemer suddenly appears behind her and the phone call is cut dead. Hastings immediately flies back to Desert Rock.
Upon arriving, he drives to the mansion, where he finds Dr. Deemer near death, suffering from severe acromegalic deformities. Deemer divulges all that he knows about the nutrient's effects on humans and animals and tells of Lund's death. Hastings returns to town to brief the sheriff on what he has learned.
As night falls, the giant tarantula comes to the mansion and attacks it. Deemer is killed by falling debris, but Steve is able to escape when Hastings returns for her in his car. The tarantula pursues them down the highway toward the town. The sheriff and his men intercept, but their guns have no effect. Dynamite is gathered from town, but a blast large enough to blow up the highway does not faze the monster arachnid. As they complete a hasty evacuation of the town, an Air Force fighter jet squadron, summoned by the sheriff, arrives and launches a napalm attack, successfully incinerating the tarantula at the town's edge.
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