The accident occurred on Interstate 405 about 3:35 a.m., KNBC-TV, Los Angeles, reported.
The California Highway Patrol said both drivers -- Yocio Gomez, 23, and Stephen Caserta, 43 -- were arrested on suspicion of driving under the influence of alcohol or drugs, the TV station said.
The victims who died were identified as Ramon Lopez, 56, of Chino Hills and Ricardo Zamora, 58, of Winchester.
A third worker suffered "minor to moderate" injuries, the Highway Patrol said. Two people in the cars involved in the crash also were hurt.
The highway workers were employees of an outside contractor hired by the state Transportation Department.