The fire was reported at 5:30 a.m. and was fought by more than 100 firefighters, with flames shooting more than 40 feet into the air and a plume of smoke visible throughout the L.A. basin.
Fire Battalion Chief Michael Bowman said firefighters were trying to confine the blaze to one building.
"We are holding check in the involved structure," he said, although he voiced frustration about getting into tight spaces where fire was burning.
The building was unoccupied and no injuries have been reported.
The Red Line subway through the area remained open, but traffic through Hollywood was at a halt.
City Councilman Eric Garcetti, who represents the area, said the property had recently been sold as part of the renovation and rebuilding in Hollywood.
Garcetti noted that today's fire is the fifth in the area in recent weeks. On Sunday, a fire apparently sparked by faulty wiring gutted a restaurant about two blocks south of Hollywood and Vine.
Garcetti dismissed any potential effect of the fires on development in Hollywood.
"We're past the point the point of no return with the Hollywood renaissance," he said.