The Vikings' twelfth game was an interconference duel with the Bills inside their dome and the first home game for interim head coach Leslie Frazier. On their first series, QB Brett Favre attempted a pass, but he was hit from behind and was intercepted by Bills CB Drayton Florence. Favre was slow to get up afterwards and he was able to walk off the field on his own power, but did not return to the game, citing a shoulder injury (later revealed to be a sprain in his throwing shoulder). At 297 consecutive starts over 19 seasons, this injury would put an end to Favre's all-time NFL consecutive start streak.  In his place, backup QB Tarvaris Jackson took over for the rest of the game. They got off to a bad start after Jackson's pass was intercepted by CB Drayton Florence and returned 40 yards for a touchdown. They overcame this deficit with Jackson getting a 31-yard TD pass to WR Sidney Rice. It was originally ruled an interception, but Frazier challenged the play and the officials sided with the Vikings, saying that Rice had two hands on the ball, resulting in a touchdown. It was followed in the second quarter by RB Adrian Peterson getting a 2-yard and a 3-yard TD run. Then Jackson found Rice again on a 6-yard TD pass, followed by kicker Ryan Longwell nailing a 38-yard field goal. They continued to dominate in the fourth quarter when Peterson ran 43 yards to the end zone for a touchdown. The Bills responded with QB Ryan Fitzpatrick getting a 12-yard TD pass to TE David Nelson. However, the Bills were unable to overcome such a large deficit and couldn't come up with another come-from-behind victory.

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