In Week 1, the Jets beat the Bills 48-28, and using point-differential logic, the 49ers should win by 54 points on Sunday.
Jokes aside, the 49ers are heavy favorites in this one and for good reason.
The Bills just allowed 52 points to the Patriots, including 45 in the second half.
Will Alex Smith and company take advantage of Buffalo's struggling defense?
Let's look at some stat predictions for Sunday's matchup.
After watching Colin Kaepernick run for 50 yards and a touchdown against the New York Jets, I'd be shocked if he didn't see the field for at least a few plays.
Still, Alex Smith should get the vast majority of the snaps against a Buffalo defense that's been getting shredded by opposing quarterbacks.
Unless either Mario Williams or Mark Anderson has a breakout performance, Smith should have a statement game that hushes the local detractors who believe Kaepernick should be featured much more in the offensive attack.
Alex Smith: 21-of-30, 256 yards, two touchdowns; one rush, five yards
Colin Kaepernick: 1-of-1, 15 yards; two rushes, 10 yards
Splitting carries with Jacobs and Kendall Hunter could decrease the load for Frank Gore, which usually results in even greater efficiency from the 49ers' top back. Expect Gore's yards-per-carry average to be near 6.0.
Hunter played his best game of the year against the Jets, rushing for 56 yards and a touchdown on eight carries.
Hunter should be able to build off last week's momentum and exploit a porous Buffalo run defense that allowed 247 rushing yards to the Patriots.
Frank Gore: 13 carries, 77 yards, one touchdown; one catch, five yards
Kendall Hunter: 10 carries, 56 yards; two catches, 12 yards
Brandon Jacobs: five carries, 19 yards, one touchdown
The Bills are allowing 269.5 passing yards per game—just what the doctor ordered for a 49ers aerial attack in need of a bounce-back performance.
Twice this season the Bills have allowed one wide receiver to catch two touchdown passes in one game (Stephen Hill and Dwayne Bowe). Overall, the Bills have allowed eight touchdowns to wideouts.
Smith nearly connected with Mario Manningham on a few long throws against the Jets. This week against Buffalo could be Manningham's breakout performance in red and gold.
Mario Manningham: six catches, 85 yards, one touchdown
Vernon Davis: four catches, 60 yards, one touchdown
Michael Crabtree: five catches, 45 yards
Delanie Walker: two catches, 40 yards
Randy Moss: one catch, 18 yards
Kyle Williams: one catch, 13 yards
The Bills defense is likely to spot the 49ers an early lead. It will be important that Buffalo head coach Chan Gailey doesn't give up on the run game, which features two explosive backs in C.J. Spiller and Fred Jackson, both of whom, according to BuffaloBills.com, are recovering nicely from their injuries.
At some point, I suspect the Bills will fall behind by two scores and become one-dimensional. This will give Aldon Smith, Ahmad Brooks and the Niners' defensive line plenty of opportunities to pressure Ryan Fitzpatrick.
San Francisco's sack total may not be all that impressive, but as long as the 49ers defense is getting pressure on Fitzpatrick, it should force multiple turnovers.
Justin Smith: four tackles
Ray McDonald: three tackles
Aldon Smith: three tackles, 1.0 sacks
Ahmad Brooks: two tackles, 1.0 sacks
Patrick Willis: eight tackles
NaVorro Bowman: nine tackles
Carlos Rogers: three tackles, interception
Tarell Brown: two tackles, interception
Donte Whitner: six tackles
Dashon Goldson: three tackles, interception
Over the last two seasons, the Bills are 2-8 on the road.
Expect their losing trend to continue against the 49ers, who have an 8-1 regular-season home record over the same span.
San Francisco's balanced offense should have no problem breaking the 30-point barrier against one of the worst defenses in the NFL.
Meanwhile, the 49ers defense hasn't allowed more than 27 points in a regular-season home game since November of 2009.
Ryan Fitzpatrick will have his fair share of success, but San Francisco's opportunistic defense will be able to force a few timely turnovers to ensure this game isn't close at the end.
San Francisco 31 Buffalo 17