The high-speed crash was reported at 5:22 a.m. just south of Slauson Avenue, according to the Los Angeles County Fire Department.
The driver of a Mini Cooper was heading south in the northbound lanes when the car struck a white van, which overturned, according to the California Highway Patrol. The male driver in the Mini Cooper died, as well as the female driver and male passenger in the van.
CHP Sgt. Manuel Rodriguez said officers were on their way after receiving reports of the wrong-way driver when the crash happened.
SIGALERT CANCELLATION IN COMMERCE: NB I-5 AT SLAUSON AVE - ALL LANES OPEN— CHP PIO - LA County (@CHPsouthern) March 12, 2017
Each person's body had to be removed from the vehicles with the Jaws of Life, according to authorities.
"When you have a head-on, you're combining speed. So if you have a vehicle traveling wrong-way at 50 mph and the other vehicle is traveling at 50 - the impact is at 100 mph," Rodriguez said.
The identities of the deceased were not immediately disclosed.
It was unclear what caused the driver to get onto the wrong side of the freeway. The investigation was ongoing.
For more than four hours, all northbound traffic being diverted off the freeway at Paramount Boulevard. The lane closure lasted until shortly after 10 a.m., the CHP said.