It happened just before 1:30 am on Highway 41 and Elkhorn Avenue, just a few miles north of Riverdale.
The California Highway Patrol says a Chevrolet Silverado was going the wrong way when it crashed with a Ford F-150.
"Just based on the physical evidence at the scene, evidence gathered, we do believe that alcohol may have played a part in this," CHP officer Mike Salas said. "Whether or not they were above the legal limit is going to depend on chemical results from the coroner's office."
Both vehicles went off the road and landed on the shoulder.
Both drivers were airlifted to Community Regional Medical Center, where the driver of the Silverado died from his injuries.
The man has not been identified.
The tragedy comes just days after Caltrans announced a $77.2 million project to transform this portion of the 41 from a two-lane highway to a divided four-lane expressway.
While the work is being done, concrete barriers have been brought in to block both sides of traffic.
Highway 41 was initially shut down but has since reopened.
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