The Patriots' fifteenth game was an AFC East rivalry rematch against the Bills. The Bills took the first possession of the game 62 yards to the Patriots 8, but had to settle for a 26-yard field goal. The Patriots drove to the Bills 46, but were forced to punt. After a Bills three-and-out, the Patriots raced 48 yards in 4 plays, taking just 1:47, scoring on a 29-yard touchdown run by Woodhead. The Bills drove to Patriots 17, but Fitzpatrick was strip-sacked by Guyton with Mayo recovering at th Patriots 20. The Patriots marched 78 yards on 9 plays, scoring on an 8-yard touchdown pass to Rob Gronkowski, increasing the lead to 14-3. The Bills drove all the way to the Patriots 32 on their next drive, but turned the ball over on downs. The Patriots continued to move the ball easily on their next drive, reaching the 16, and Graham kicked a 34-yard field goal, increasing the lead to 17-3. On the fourth play of the Bills next drive, Fitzpatrick was intercepted at the Bills 46 by Chung who returned it 19 yards to the Bills 27. Seven plays later, Brady hit Alge Crumpler on a 4-yard touchdown pass, widening their lead to 24-3 at halftime. After a Patriots three-and-out, Fitzpatrick was intercepted by Page at the Bills 21. A chop block penalty on Chad Reinhart moved the ball to the Bills 11. Four plays later, Brady hit Gronkowski on an 8-yard touchdown pass, making the score 31-3. The Bills drove to the Patriots 22 on their next drive, but turned the ball over on downs. Early in the fourth, Graham hit a 26-yard field goal, making the score 34-3. The Bills turned it over two more times and punted every other time as the Patriots cruised to a dominating win. With the win, New England improved to 13-2, clinched the AFC East along with the number one seed and homefield advantage throughout the playoffs. Brady had his ninth consecutive game without an interception, and in the process broke Bernie Kosar's record of pass attempts without an interception (308, from 1991-1992). It was also his eighth consecutive game with at least two touchdowns and no interceptions.

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