The San Francisco 49ers open a home-heavy portion of their schedule following an impressive win.

The Buffalo Bills could use one of those as they begin a potentially rough stretch outside of western New York.

San Francisco goes for a sixth straight home win over an AFC opponent when the Bills try to end a five-game road skid against NFC foes Sunday.

Coming off a surprising 24-13 loss at Minnesota, the 49ers (3-1) routed the New York Jets 34-0 last Sunday for their first road shutout since Jan. 6, 2002, against New Orleans.

San Francisco is hoping all three phases are clicking again this week after holding the Jets to 145 total yards, recovering three fumbles, blocking a punt and rushing for a season-best 245 yards.

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"This is more the way we are accustomed to playing," coach Jim Harbaugh said.

The 49ers can get used to playing at Candlestick Park as they'll play three straight and five of six in the Bay Area. A 27-19 winner over Detroit in its lone home game this season, San Francisco has not lost to a visiting AFC team since Nov. 8, 2009, against Tennessee.

If the Bills (2-2) are going to change that - and win their first game in an NFC stadium since Oct. 25, 2009, versus Carolina - they'll have to move past last Sunday's 52-28 loss to New England. But after committing a season-high six turnovers and giving up the second-most yards in team history with 580, there's no telling how much of an effect the defeat will have on the team this weekend.

"It's one that will hang with us," said Ryan Fitzpatrick, who threw four touchdowns and a season-high four interceptions. "You try to block it out with Chan's (coach Gailey) 24-hour rule and all that, and you hope it doesn't linger into the next game."

If it does, Gailey's team will have little chance to leave San Francisco with a victory. And it doesn't get any easier after this game, as Buffalo will play three of its next four on the road, including stops in Arizona, Houston and New England.

"I've got to work on the mindset of this football team and creating a sense of urgency every snap of every game," Gailey said Monday.

Part of that means Fitzpatrick has to make better decisions, as his seven interceptions are among the most in the NFL. However, he could be under plenty of duress as the 49ers' defensive front will face a Buffalo line without injured starters Cordy Glenn and Kraig Urbik.

Under coordinator Vic Fangio, San Francisco's defense has limited opponents to 3.2 yards per carry after the Jets totaled 45 yards on 17 rushes last Sunday.

The Bills might have one of the deepest backfields in the NFL with Fred Jackson, C.J. Spiller and Tashard Choice, but Jackson and Spiller are coming off injures and both lost fumbles last week when Buffalo finished with a season-low 98 yards on the ground.

Coming off their best rushing effort of the season, the 49ers could get a boost if Brandon Jacobs makes his team debut. The former New York Giant has been sidelined since suffering a knee injury in the second preseason game.

"I'm ready to play," he told the 49ers' official website Tuesday. "It's nothing now, it's all gone."

Even if Jacobs has to wait another week to get in, Frank Gore and Kendall Hunter could have big days against a Bills defense that surrendered 247 yards and four TDs on the ground last week. Buffalo had not allowed that many rushing scores at home since 1977.

"When you have two guys rushing for 100 yards, something's up," end Mario Williams said. "We have to have a reality check and see what's going on."

The Bills are hoping to bounce back just like the 49ers did last week when they stayed in Youngstown, Ohio, following the Vikings loss.

"For sure, the whole week there was more of an edge - it was just a bad taste in your mouth," said Alex Smith, who had season lows of 21 attempts, 12 completions and 143 yards while not throwing a TD against the Jets. "I don't think that goes away in one day. We wanted to be 3-1 and got it done."

These teams have alternated wins and losses in the last seven meetings with the road team winning the last two. The 49ers left Buffalo with a 10-3 victory in the last matchup Nov. 30, 2008.