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The chain reaction of collisions shut down Interstate 25km west of Beaumont for several hours, said Deputy Rod Carroll of the Jefferson County Sheriff's Office.
"We have 18-wheelers on top of cars, we have cars on top of cars. It's just catastrophic," he said, adding that rescuers were still looking for victims.
Two bodies were found underneath a tractor-trailer, he said. Eighty to 120 people had been taken to hospitals, and eight to 10 of them were seriously hurt, Carroll said.
He said the initial accidents took place separately about 1.5km apart on the east- and westbound sides of the interstate.
The highway had been crowded with motorists traveling during the Thanksgiving holiday. Many of the vehicles were moving close to the posted speed of 110kmh despite dense fog that limited visibility, Carroll said.
The westbound lane of the interstate has been reopened, he said.