I-20 near Midland International Airport reopened Thursday night.
Names of the four victims in three vehicles were not immediately released. Authorities say the driver of a fourth vehicle survived.
Midland Fire Department official David Hickman says debris from Thursday afternoon's wreck ended up more than 100 feet from the highway.
The Department of Public Safety says a tractor-trailer rig traveling east on I-20 apparently went off the road and hit a westbound 18-wheeler. Officials say a truck hauling cattle then drove through the fiery scene and crashed.
DPS says a pickup then hit some boxes of produce being hauled by one of the big rigs. The pickup driver survived.