ORCHARD PARK, N.Y. Christian McCaffrey exited Sunday nights game against the Bills with a knee injury to suddenly halt the best start of his already truncated 49ers season.

McCaffrey, on his seventh carry of this snowy night, ran to his right, intentionally slid for a 5-yard loss at the Buffalo 34-yard line. After a 5-minute exam in the 49ers’ sideline medical tent, he jogged into the locker room, with his right sock pulled down to his ankle.

Last season’s NFL Offensive Player of the Year, McCaffrey missed the first two months of this season (eight games) because of Achilles tendinitis.

This was his fourth game back, and he racked up 58 yards on his first six carries, including season-long gains of 19 and 18 yards.

He appeared to hurt his knee by landing hard on Highmark Stadiums synthetic (and chilly) turf, having been tripped up by safety Taylor Rapp to end an 18-yard run 12:15 before halftime.

The 49ers listed him as questionable to return. McCaffrey also had two receptions for 14 yards for the upset-seeking 49ers (5-6).

The 49ers jumped out to a 3-0 lead on their first possession, which included a third-down conversion and later a 19-yard run by McCaffrey.

McCaffrey’s injury came just after a Bills penalty nullified an interception of a Brock Purdy pass; that 49ers drive ended in a missed field goal by Jake Moody.

The injury-laden 49ers were without linebacker Fred Warner (cramps) when the Bills’ James Cook scored on a 65-yard run to open their drive that followed McCaffrey’s exit.