Leon arrives in the small town of San Miguel in southern Arizona only to find that most of the town has been brutally slaughtered. He is confronted by Samantha, a police officer from the neighboring town of Palo Verde, who is responding to a distress call. They quickly find themselves under attack by a pack of bloodthirsty Chihuahuas with the strength to back up their vicious attitudes. Unfortunately for Samantha, Leon's only fear in the world is Chihuahuas. Leon and Samantha encounter the few survivors left in town, including Johnny, the rowdy redneck who is hunting the dogs, and Erica, a young waitress accompanied by her part-Chihuahua puppy. They arrive at the Mayor's house and quickly find themselves trapped there with him. Samantha begins to suspect that some of the survivors may know more than they're letting on and that one or more of them may have something to do with the Chihuahuas attacking them. With an army of Chihuahuas surrounding them and all hope of escape cut off, the survivors prepare for a fight to the death in the Mayor's house, after which only one species can claim status as the reigning king of the food chain.
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