Fred Jackson missed the final six games last season with a broken leg. On Sunday, he suffered another leg injury that took him out of the game.
The running back exited the Buffalo Bills' season opener against the New York Jets after suffering a lower leg injury during the first half at MetLife Stadium.
CBSSports.com's Jason La Canfora reported the initial diagnosis is a sprained lateral collateral ligament in Jackson's knee.
The Bills later announced Jackson wouldn't return.
Jackson took a handoff off right tackle with 11:17 remaining in the second quarter before he was taken down low by Jets safety LaRon Landry. Jackson attempted to walk it off on the Bills' sideline, but he later was seen walking gingerly toward the locker room with two trainers.
C.J. Spiller replaced Jackson and busted a 56-yard touchdown run on his third carry. If Jackson is forced to miss extended time, Spiller could be in position to steal carries once Jackson returns.
UPDATE: Jackson will undergo an MRI to determine the severity of the injury. The Bills also lost wide receiver David Nelson in the fourth quarter, and ProFootballTalk reports the team fears he has suffered a torn anterior cruciate ligament.
"Both of them were knees," coach Chan Gailey told the Bills' official website. "Fred doesn't look as bad as David (Nelson). We don't know how bad David is, but it doesn't look good right now. Fred doesn't look nearly as bad, but we're going to get a further evaluation tomorrow."
Jackson later on Twitter thanked fans for their support.
#BillsMafia Thanks for all the prayers all well wishes. I will get back on field ASAP! Keep Billieving in us, jus more work to do!!â Fred Jackson (@Fred22Jackson) September 9, 2012
Follow Dan Hanzus on Twitter @danhanzus.