ST. LOUIS (AP) San Francisco linebacker Patrick Willis left Monday night's game at St. Louis in the third quarter with a toe injury and is not expected to return.
Willis, a seven-time Pro Bowl selection, leads the 49ers with 44 tackles this season. He had three more before leaving the game against the Rams.
Rookie Chris Borland replaced him.
The Niners are already without linebacker NaVorro Bowman, who was hurt in last season's NFC championship game.
Willis leads the NFL in tackles over the past seven seasons.
San Francisco also lost backup safety Jimmie Ward to a quad injury in the third quarter, and the team said he would not return. Starting guard Mike Iupati was taken to the locker room for tests after he suffered a head injury in the final two minutes of the quarter.