It happened at about 10:20 pm on Highway 43, just North of Davis Avenue.
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The rural area is Southwest of Kingsburg.
The California Highway Patrol says a Toyota Camry was heading South when it crossed over the center line to pass traffic but instead crashed with a Range Rover heading North.
The 18-year-old driver and 15-year-old passenger in the Camry died at the scene.
A second passenger in the Camry and the two people in the Ranger Rover were taken to the hospital.
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Officials say marijuana drug use by the two teens is suspected.
The man driving the Range Rover is 57 years old and was seriously injured.
The crash is under investigation.