The wreck was first reported shortly before 5:20 p.m. on Highway 29 just south of Grange Road, north of Middletown and near the Crazy Creek gliderport.
The California Highway Patrol said two sedans — one black, one white — were involved.
Shortly after firefighters arrived on scene, they reported over the radio that one person had died, with another patient suffering minor injuries.
The highway remained open but the CHP warned of potential delays.
Additional information about the crash and its cause was not immediately available.
The wreck was the second fatal crash in Lake County this week.
On Wednesday, a crash near Blue Lakes on Highway 20 killed a Lakeport man, as Lake County News has reported.
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