After the victory over Miami, the Bills stayed home for a Week 16 intraconference game with the Tennessee Titans. The Titans (like the Bills) were 7-7 and also hunting for a wildcard berth. In the first quarter, Buffalo scored first with kicker Rian Lindell getting a 21-yard FG. Tennessee would respond with Vince Young completing a 22-yard pass to Bobby Wade. The Bills came back with Willis McGahee's 1-yard TD run. In the second quarter, the Titans regained the lead with kicker Rob Bironas getting a 42-yard and a 20-yard FG. Afterwards, the Bills came back with Lindell kicking a 36-yard and a 45-yard FG. Then, Tennessee went back into the lead with Young's 36-yard run. Buffalo would score with another 21-yard FG from Lindell, this one before halftime. In the third quarter, J. P. Losman completed a 37-yard pass to Lee Evans and afterwards Lindell kicked a 24-yard FG. In the fourth quarter, the Titans won the game with Young completing a 29-yard pass to Brandon Jones and Bironas' fifth FG of the game, a 30-yarder. J. P. Losman led the Bills on one final drive down to the Titans' 28-yard line, but driving against a wind that was gusting up to 20mph, the Bills elected not to try a potential game-winning FG, sealing the game for the Titans. With the loss, not only did the Bills fall to 7-8 in their final home game of the season, but they were also eliminated from playoff contention heading into the season finale.

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