It happened at around 2 a.m. Sunday along Highway 74 and Hammack Avenue, just northeast of Lake Elsinore.
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Officials with the Riverside County Fire Department told ABC7 they received multiple calls regarding a wrong-way driver. Soon after, they began receiving reports of the crash.
Investigators said one person from each vehicle died.
The remaining two were rushed to the hospital, one of whom had serious injuries.
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Investigators believe speed played a role in the crash, though it's unclear what exactly caused the collision.
The incident remains under investigation.