Manning underwent more neck surgery Thursday, his third procedure in 19 months, and his return this season is uncertain.
Losing Manning for any stretch of time is something the Colts would love to avoid, and it's certain to throw the race for the AFC South wide open.
Manning hasn't missed a game in 14 NFL seasons, with 227 consecutive starts, including the postseason.
"Rehabilitation from such surgery is typically an involved process," the team said in a statement, calling the procedure "uneventful."
The Colts said there would be "no estimation of a return date at this time. We will keep Peyton on the active roster until we have a clear picture of his recovery process."
Team owner Jim Irsay tweeted that the 35-year-old Manning would be out "awhile."
I'm hesitant to start talking "career" in terms of Peyton Manning, only because I remember people saying the same thing about Dan Marino only to see him come back and erase all memories of Scott Mitchell.
That said, this sound serious, and at 35 you have to wonder. It saddens me about the season, because I got a lot of joy out of watching Manning play. I don't think I've ever seen a football player dominate throughout a season like he did in 2009.