It happened before 2 am at the intersection of Highway 137 and Road 68, west of Tulare.
Investigators say the driver of a Nissan Pathfinder was southbound on Road 68 when he failed to stop at the intersection. The SUV broadsided an oncoming Chevy Silverado traveling east.
The CHP said the driver of the Nissan was not wearing a seatbelt. He was thrown from the vehicle and died at the scene.
The driver of the Chevy suffered major injuries in the crash. He was taken to Kaweah Health Center for treatment.
CHP officers are working to determine what led up to the crash. It's unclear if drugs or alcohol were factors.