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A documentary film crew headed by anthropologist Steve Cale (Eric Stoltz) and director Terri Flores (Jennifer Lopez) travel down the Amazon River in search of a mysterious Indian tribe. On their journey they save a man, Paul Sarone (Jon Voight), from a sinking boat. He offers to help in their search for the tribe, but he is actually a snake-hunter looking for the legendary Anaconda snake. When an accident leaves Cale unconcious, Sarone takes charge of the boat, leaving the rest of the crew in grave danger.