The fatal crash was reported at 12:30 p.m. at Sneath Lane. The alert was issued at 1:10 p.m., CHP Officer James Evans said.
The CHP has since closed the westbound Interstate Highway 380 exit onto El Camino Real.
The accident involved many vehicles and left at least one person dead, Evans said.
San Bruno police also responded to the fatal crash, Evans said. The CHP did not have an estimate when the area would reopen.
Officials advised avoiding northbound El Camino Real because of long delays expected in the area.