Guard Richie Incognito knewLeSean McCoy's right knee was fine when the Bills running back was already gabbing in Buffalo's locker room during halftime.
"As long as Shady's talking, he's fine," Incognito said.
If knocking knees with 49ers linebacker Nick Bellore late in the first half couldn't slow down the player nicknamed, "Shady," what chance did the 49ers porous run defense have?
McCoy had 140 yards rushing and matched a career high by scoring three times, and the Bills extended their winning streak to four with a 45-16 victory over San Francisco and new starter Colin Kaepernick Sunday.
Buffalo fans greeted Kaepernick roughly for his leadership among athletes protesting during the national anthem. They booed him loudly, sold anti-Kaepernick T-shirts and roughed up a dummy wearing his jersey.
Kaepernick finished 13 of 29 for 187 yards, including a 53-yard touchdown pass to Torrey Smith. But San Francisco (1-5) couldn't finish drives, settling for three field goals by Phil Dawson, in losing its fifth straight game.
"I thought he was OK," coach Chip Kelly said of Kaepernick, whom he promoted over Blaine Gabbert following a 33-21 loss to Arizona. "But overall, offensively as a group, we need to run the ball better and we need to be better at the passing game."
Kelly wouldn't commit to who will start next week against Tampa Bay.
"Yeah, we'll see," he said.
Tyrod Taylor threw two touchdown passes in helping Buffalo win four straight for the first time since the start of the 2008 season.
The 49ers allowed 312 yards rushing - Buffalo's best outing since 1992. The defense has allowed 981 yards on the ground in its past five games.
The Bills blew the game open by scoring 21 points over a span of 7:02 straddling the third and fourth quarters.
Taylor completed a 30-yard pass to Justin Hunter . Then the 49ers were stopped for no gain on a fourth-and-1 at Buffalo's 40.
After McCoy put the Bills up 31-16 with 10:53 left in the fourth quarter, the Bills got the ball back on afterKeshawn Martin fumbled the kickoff.
Two plays later, Taylor hit Robert Woods for a 5-yard touchdown pass.
McCoy scored twice on 18-yard runs and another on a 4-yard scamper in his second meeting against Kelly. McCoy expressed bitter feelings toward Kelly for trading him from Philadelphia to Buffalo.
"To sit here and tell you that it didn't affect me last year, I would be lying," McCoy said. "But I'm past that. It's a whole year later."
McCoy's 3-TD game was the third of his career, and first since Philadelphia's 45-19 win over the Rex Ryan-coached Jets in 2011. He became Buffalo's first player to score three times rushing since Willis McGahee had four TDs against Seattle in 2004.
Backup Mike Gillislee closed out the scoring with a 44-yard run. Buffalo's 45 points were the most since a 49-31 win at Cincinnati in 2010.
Bills LB Lorenzo Alexander extended his sack streak to six games, matching the team's longest since Aaron Schobel did it during the 2006 season. The 10-year journeyman now has eight sacks this year.
With three sacks on Sunday, Buffalo upped its total to 20 - one fewer than the team had all last season.
Fans chanted "USA! USA! USA!" shortly before Kaepernick knelt for the anthem.
"To be honest, I was focused on football so I really wasn't listening to what was going on in the stands," Kaepernick said.
Outside New Era Field, one vendor was selling T-shirts against Kaepernick.
Buffalo's defensive backfield left Smith wide open in scoring on his 53-yard catch and run . CornerbackStephon Gilmore let Smith blow past him at the line of scrimmage leaving Smith open up the right sideline. He easily caught Kaepernick's pass and then cut into the middle to avoid being tackled by safety Aaron Williamswho was Buffalo's only defender deep.
49ers: Host Tampa Bay on Oct. 23.
Bills: Play at AFC East rival Miami on Oct. 23.