The solo-vehicle crash was reported at 1:20 p.m. near Millbrae Avenue, CHP Officer Kevin Kroncke said. It is unknown what caused the vehicle to overturn and catch fire.
Two people were pronounced dead at the scene. The status of the other two is unknown, CHP Officer Grace Castillo said.
Two lanes of northbound 280 are expected to remain closed until at least 4 p.m.
The fire burned one-half acre.
ABC7 News contributed to this report