The Bills are coming off a 52-28 loss to the New England Patriots in Week 4 in which they allowed two 100 yard rushers and two 100 yard receivers in the same game. The 49ers have the league's third ranked rushing attack at 167 yards/game and the Bulls defense ranks 28th against the run, giving up 137 yards a game.
Bills' quarterback Ryan Fitzpatrick will look to minimize mistakes after he threw for four interceptions to go along with four touchdown passes against the Patriots. Fitzpatrick will face a stingy 49ers' defense that ranks fifth in passing and rushing this season.
At 3-1, the 49ers currently sit in second place in the NFC West behind 4-0 Arizona. The Bills are tied with the Patriots and Jets at 2-2 in the AFC West.
The eight point spread is the second largest of the week as the Houston Texans are favored over the New York Jets by nine points.