The San Francisco 49ers will be without their two best running backs for the foreseeable future.

Starter Christian McCaffrey will be placed on injured reserve due to a PCL injury in his right knee and top backup Jordan Mason will be placed on IR with a high ankle sprain, coach Kyle Shanahan announced Monday.

McCaffrey’s injury requires an expected recovery period of six weeks. He will not require surgery, Shanahan said.

Rookie Isaac Guerendo will now take over the starting role for the 49ers, who fell to last place in the NFC West after their loss to the Buffalo Bills on Sunday night at 5-7.

Sunday night was just McCaffrey’s fourth game since returning from bilateral Achilles tendonitis, which kept him out for most of training camp and all of San Francisco’s first eight games. He ran for 53 yards on seven carries before leaving with his injury Sunday night.

Mason skillfully filled in for McCaffrey while he was out on the road Sunday evening. He finished the game with 13 carries for 78 yards, and Guerendo scored the Niners’ only touchdown of the night, shooting down the left side from 15 yards out.

Mason leads the 49ers in rushing this season with 789 yards and has scored three touchdowns, while McCaffrey has 202 yards in shortened action. He hasn’t scored a touchdown in four games after scoring 21 total touchdowns in 2023.