The crash was reported at 6:08 a.m. on Highway 24 by Wilder Road, CHP Officer Kevin Bartlett said.
Two people were transported to a hospital to be treated for major injuries, but Bartlett said he was unsure whether the injuries are considered life threatening.
Bartlett said a big-rig lost a trailer and around five cars hit the trailer, causing the blockage.
The CHP did not issue a Sig-alert, although all lanes were blocked for more than an hour, backing up traffic to the Caldecott Tunnel, Bartlett said.
At about 7:20 a.m., three lanes reopened, and by 8:12 a.m., all lanes reopened, Bartlett said.