Coming off a road win over the Chiefs, the Bills went home for a Week 13 interconference duel against the San Francisco 49ers. In the first quarter, Buffalo trailed early as 49ers QB Shaun Hill completed a 12-yard TD pass to WR Isaac Bruce. In the second quarter, the Bills continued to trail as kicker Joe Nedney made a 50-yard field goal. In the third quarter, Buffalo tried to rally as kicker Rian Lindell nailed a 22-yard field goal, but the team struggled offensively for the rest of the game. QB Trent Edwards (10/21 for 112 yards) didn't play the second half, due to a groin injury.

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