49ers RB Frank Gore could have a big day against a Buffalo defense that has struggled stopping the run. (US Presswire)

Bills at 49ers -- Week 5

Where: Candlestick Park, San Francisco (grass, outdoors)

When: Sunday, 4:25 p.m., ET (CBS)

Spread: 49ers by 9.5

Forecast: Mild, 60 degrees, mixture of sun and clouds

Records: Bills (Overall: 2-2, AFC East: 0-2); 49ers (Overall: 3-1, NFC West: 0-0)

Past results: Two most recent meetings -- Nov. 30, 2008: 49ers 10, Bills 3; Dec. 26, 2004: Bills 41, 49ers 7. Series record: Tied 5-5.

What matters: Buffalo has an impressive backfield combination of RB C.J. Spiller (41 carries, 341 yards, 3 TDs) and RB Fred Jackson (900-plus yards in each of the past three seasons), but San Francisco ranks No. 6 in the NFL in rushing defense. Minnesota showed in Week 3 the formula to beat San Francisco starts with having success in the passing game, so the onus is on Bills QB Ryan Fitzpatrick to keep the defense honest. 49ers defensive coordinator Vic Fangio has been mildly impressed by Fitzpatrick, who is coming off a game in which he threw for 350 yards but four INTs against New England. “I think he’s a competent NFL quarterback. He makes good decisions,” Fangio said. “He gets a quick read on the defense. He gets the ball out pretty quick.”

Who matters: Offensive coordinator Greg Roman. Roman has done a good job keeping the 49ers' offense balanced and unpredictable. RB Frank Gore has been the one constant, but Roman has found ways to get several players involved week to week. WRs Michael Crabtree, Mario Manningham and Randy Moss have had their moments, and TE Vernon Davis has remained one of QB Alex Smith’s primary targets. Based on the Bills’ struggles stopping the run (28th in the NFL), Gore figures to be leaned on heavily, but that doesn’t necessarily represent a change from the ordinary.

Key matchups: 49ers OLB Aldon Smith and DL Justin Smith vs. Bills LT Chris Hairston. With Buffalo starting LT Cordy Glenn out with an ankle injury, Hairston steps into the starting lineup for the first time this year. The injury to Glenn couldn’t have come at a worse time for the Bills as Smith and Smith represent possibly the best right side in the NFL.

Injuries of note: RB Brandon Jacobs is expected to make his 49ers' debut and the team isn’t expecting anyone to miss the game due to injury. LT Glenn (ankle), RG Kraig Urbik (ankle) and DT Spencer Johnson (ankle) are out for Buffalo.

Inside stuff: San Francisco has gained at least four yards on 70 of 122 first-down plays this year -- the most in the NFL.

Connections: Bills S Delano Howell played for Harbaugh at Stanford and started alongside 49ers practice-squad S Michael Thomas for the Cardinal the past two seasons. 49ers S Donte Whitner was drafted by Buffalo in the first round of the 2006 NFL Draft but said this week he wasn’t a good fit in the team’s Tampa-2 defense.

Stat you should know: The 49ers have not allowed a rushing TD in 11 straight home games, the NFL's best mark during that span.

Looking ahead: San Francisco will host the New York Giants in Week 6 in a rematch of last season’s NFC Championship before it plays its first NFC West game the following Thursday against Seattle. Buffalo will take a page out of the 49ers’ book and remain in the Pacific time zone next week before its game at Arizona. The Bills will practice at Arizona State in Tempe.

Prediction: 49ers 27, Bills 13

Follow 49ers reporter Kyle Bonagura on Twitter @CBS49ers and @KyleBonagura.

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