Brady has a 26-3 career mark facing the Bills, with the 26 wins tying Brett Favre for most ever by a starting quarterback against a single opponent. Favre's 26 victories came against the Detroit Lions.
A victory Sunday at New Era Field would put Brady alone atop the ranks with 27 wins against the Bills.
Here's the rest of the top five:
Favre -- 26 (vs. Lions)
Brady -- 24 (vs. Jets)
Favre -- 23 (vs. Bears)
Dan Marino -- 22 (vs. Colts)
That Brady, 40, is on the verge of such a record is a reminder of how long he has remained at the top of his craft (while also showing little to no signs of decline). His lifetime stat line against the Bills: 610-of-955 for 7,316 yards, with 66 touchdowns, 20 interceptions and a passer rating of 101.5.
Sunday will mark Brady's fifth December game in western New York, with the first coming in 2001 and proving to be one of the most memorable. In a 12-9 overtime victory on Dec. 16 of that season, wide receiver David Patten had fumbled along the sideline and was knocked out briefly on the play, but because his head was out of bounds and the ball was still touching him, the Bills couldn't recover it legally.
So the Patriots maintained possession and went on to kick a game-winning field goal.
Brady, who at the time was in his first year as a starter, finished 19-of-35 for 237 yards and no touchdown passes, which marked the third straight contest he didn't throw a scoring pass. He was also sacked five times.
Perhaps with that game in mind, Brady said Monday on Westwood One Radio, "Going to Buffalo late in the season, it's always a tough place to play."
Brady then cited the Bills' most recent game, a 16-10 victory over the Chiefs at Arrowhead Stadium, where the Patriots were crunched 41-14 in the 2014 season in a game that sparked Bill Belichick’s now-famous "on to Cincinnati" refrain.
Setting up this year's Patriots-Bills matchup, Brady said on Westwood One, "They've got a lot on the line. So do we. They went on the road and beat the Chiefs at Kansas City. We know how tough that is. They're going to give us everything we can handle on Sunday."
And, in turn, Brady will do the same as he looks to separate himself from Favre in the record books.