- RB Bryce Brown (healthy scratch)
- TE Lee Smith (toe)
- OT Cyrus Kouandjio (healthy scratch)
- OG Cyril Richardson (healthy scratch)
- DE Jacquies Smith (healthy scratch)
- CB Stephon Gilmore (groin)
- S Jonathan Meeks (neck)
Gilmore's unavailability is a big blow as the team takes on the Bears' enormous and talented receiving corps in Week 1. Corey Graham will likely get the start opposite Leodis McKelvin, with Nickell Robey serving in a nickel capacity; the team will be okay so long as all three of those corners can finish the game.
There is not, apparently, room for a fourth running back in Buffalo; Brown is a healthy scratch while teammate Anthony Dixon, who was questionable with a hamstring injury, will dress and serve not only as the third running back, but as a key special teams figure.
Lee Smith left the Bills' preseason finale on August 28 with a toe injury, and has not practiced since. That leaves the Bills without one of their more critical run and pass blockers against an improved Bears front four; Scott Chandler will see a bit more playing time as a result, and Chris Gragg will fill the second tight end role as needed.
Kouandjio and Richardson, two of the team's three offensive line draft picks, will sit in favor of a better-prepared swing tackle option (Chris Hairston) and a more versatile interior reserve (Kraig Urbik), respectively. On the other side of the line, the team can sit Jacquies Smith in favor of Jarius Wynn, who is a bit more stout against the run.
Meeks has not played since the first full week of the preseason with a neck injury, and only just returned to practice this week. That leaves the Bills with just three safeties in this contest, and as it's looking like all three will see playing time, the team's emergency plan at that spot will likely involve Graham, who again is starting for Gilmore.