The crash happened around noon in Fresno County on Highway 180 near Fulton Street.
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Officers say for an unknown reason a station wagon and a sedan collided on the right-hand shoulder of the freeway.
Both cars went through the guard rail.
Investigators say several people were hospitalized but it's unclear what led up to the crash.
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Those taken to a hospital had moderate to major injuries.
The crash slowed down traffic in the westbound lanes for hours.