Alex Smith was nearly perfect through the air, Frank Gore had his way on the ground and the San Francisco 49ers defense again kept the opposition out of the end zone in a 45-3 shellacking of the Buffalo Bills.
Smith connected on 18-of-24 passes for 303 yards and three touchdowns, while Gore ran for 106 yards and a score on 14 carries for the 49ers (4-1), who gained a franchise-record 621 yards in their second straight blowout victory.
"When you think of the 49ers, you think of great offense, so it's quite an honor," Smith said of the team record. "It was a great team victory."
San Francisco beat the Jets in New York, 34-0, in Week 4 and scored the final 42 points Sunday to win going away.
Michael Crabtree caught six passes for 113 yards and a TD, and Vernon Davis added 106 yards on five receptions in the rout.
Ryan Fitzpatrick finished with just 126 yards and an interception for Buffalo (2-3), which came in with an NFL-high 16 touchdowns but gained just 10 first downs in its second straight debilitating setback.
The Bills gave up 45 second-half points in last week's loss to the Patriots and again had no answer for a 49ers team clicking on all cylinders.
"Obviously there's something I'm not doing correctly with this football team in the second half, because we've played extremely poorly, and that's as nice as you could put it, in the second half," Bills head coach Chan Gailey said. "I don't have the answers today. I have to find the answers."
Sunday's game shifted five minutes into the second quarter when Smith found Kyle Williams down the right sideline. Williams was tightly covered, but came back for the underthrown pass and made two defenders miss en route to a 43- yard TD that broke a 3-3 tie.
The 49ers were moving deep into enemy territory the next time they had the ball, but backup quarterback Colin Kaepernick fumbled on an end around.
Buffalo took over at its own 17-yard line with 46 seconds remaining in the half, and rather than run out the clock, tried to move the chains.
The decision backfired, as 49ers linebacker Patrick Willis stripped tight end Scott Chandler after a modest gain. Dashon Goldson recovered the fumble at the Buffalo 28 with 29 seconds to go, and on the next snap, Smith found Crabtree on a post-corner route at the left pylon for a 17-7 halftime lead.
Momentum continued going the hosts' way after the break. Smith and Davis connected for a 24-yard gain to get across midfield, and Gore shredded the defense for a 31-yard gain. Kaepernick took a keeper himself for 15 yards to the one, and Gore dove over the goal line with 5:54 gone in the third.
Chris Culliver's interception of Fitzpatrick preceded a 13-play, 94-yard drive that was capped with Mario Manningham's 10-yard TD catch in the opening minute of the fourth quarter.
Kaepernick and Anthony Dixon later added rushing touchdowns for good measure.
The Bills hurt themselves the first time they touched the ball, as a holding penalty negated Leodis McKelvin's 80-yard punt return for a touchdown.
An early 19-yard field goal by David Akers gave the 49ers the lead, and Buffalo tied it on Rian Lindell's 31-yard kick in the second quarter.
Smith, who was seven passing yards shy of his career high, finished with a 156.2 quarterback rating. The 49ers are 13-0 when Smith has a 100-plus QB rating ... San Francisco, which had 29 first downs, has won six straight home games against the AFC ... Bills running back Fred Jackson was held to 29 yards on nine carries ... Buffalo had 204 total yards.