At least 85 position were eliminated at the Fontana and Ontario medical centers, officials said Friday.
Officials at the health-care provider did not release the locations of the other 445 positions.
The layoffs do not include physicians.
"We expect that over the next year we will experience significant membership growth and anticipate that many of these affected employees will have new opportunities to be placed in other positions and remain with our organization," said Peggy Hinz, spokeswoman for Kaiser Permanente.
Kaiser officials said they have undertaken a series of layoffs to ensure they meet possible changes that could occur with the implementation of President Obama's Affordable Care Act, which aims to make sure every American has health care coverage.
Late October, Kaiser laid off 84 non-union employees, which they called a "modest downsizing of staff" in Southern California.
United Steel Workers Local 7600 President Roy Wiles spent his Friday notifying employees they no longer had a job with Kaiser. The union represents clerical, patient care and service workers in the Inland Empire.
"I've done this a long time. I don't think it's ever easy," Wiles said.
"It's very difficult for all the employees."
The Kaiser employees will be able to take advantage of the union's income-protection program that is set up to help find retaining, education and possibly another job at Kaiser, which Wiles said has been successful in the past.
As of Oct. 30, Kaiser facilities in Southern California had 60,000 staff members and 5,700 physicians.
Staff writer Ryan Carter contributed to this report.