The driver was heading east on Interstate Highway 780 with two passengers in the car when he lost control and veered into a guardrail at about 12:40 a.m., the CHP said.
The car then spun around and into the path of a red Kia Rio heading west, the CHP said.
The Kia hit the Camry, veered off to the right and went 20 feet off the road. The woman driving was unharmed, the CHP said.
The man driving the Toyota was pronounced dead there, while his two passengers were taken to a hospital with minor injuries.
Investigators are looking into the possibility that the man may have suffered a medical condition while driving causing him to lose control of the car, the CHP said. Drugs and alcohol do not appear to be a factor in the crash.
The CHP initially reported that a person in the Kia had died but later clarified that the driver of the Toyota was the only fatality.
The connecter between I-680 and I-780 was closed in both directions until shortly after 3 a.m., disrupting traffic coming to and from the Benicia-Martinez Bridge.