The head-on collision occurred shortly before 2:30 p.m. in the area of Highway 121 near Napa Road, according to the California Highway Patrol.
The crash involved a blue Honda versus a white pickup, with the pickup upside down and blocking part of the roadway, causing the road to be shut down, the CHP reported.
The CHP, fire and Napa County Sheriff's officials responded to the scene, where two people were reported trapped.
Shortly after the crash, one death was confirmed. The CHP reported that a second death was confirmed just before 3 p.m.
Caltrans set up a detour around the site as the investigation continued and the coroner came to deal with the fatalities, the CHP said.
Further details on the victims and the cause of the crash were not immediately available Sunday.
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