The California Highway Patrol said the crash happened around 6 p.m. near Allendale Road, about nine miles north of Vacaville.
The driver of the Prius died and the Subaru driver was rushed to the hospital with major injuries, but is stable, the CHP said.
All southbound lanes are blocked at Allendale Road and traffic was diverted off at Putah Creek. It's unknown when the highway will reopen.
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