Roethlisberger wore a custom-made ankle brace that stretched up his calf while warming up before Monday night's game at San Francisco. He last missed a start due to injury in 2009.
San Francisco linebacker Patrick Willis was inactive for the second straight game with a right hamstring injury. Receiver Braylon Edwards has been hampered by a surgically repaired right knee and missed his third straight game.
Pittsburgh linebacker James Harrison was serving a one-game suspension for a helmet to facemask hit on Browns quarterback Colt McCoy on Dec. 8, and center Maurkice Pouncey was inactive with a sprained left ankle.
Information from The Associated Press contributed to this report.