The crash, involving seven vehicles, a truck, occurred near Butterfield Ranch Road around 8:15 a.m. when a box truck toppled over on top of a sedan, according to the California Highway Patrol.
Two women who were traveling in a white car died, and a 15-year-old who was also in the vehicle was injured, authorities say.
AIR7 HD was over the scene, where all southbound lanes were blocked for several hours. All lanes were reopened at 12:30 p.m.
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It appeared several vehicles were mangled in the collision, including the vehicle crushed by the big rig.
Five other people were hurt in the incident.
"I ran over to the people in the white car, and the kid that was in the white car - I felt horrible for him," one witness said.
The cause of the crash is not yet clear. Officials said no skid marks were found at the scene.
The driver of the box truck, who is believed to have caused the crash, will be interviewed by authorities.