With both squads narrowly holding first-round byes in the playoffs, this game has enormous postseason implications for both divisions.
Here's your rundown for Sunday:
Where: Gillette Stadium, Foxborough, M.A.
When: Sunday, Dec. 16 at 8:20 p.m. ET
Live Stream: NFL Game Rewind
Spread: Patriots (-5) (via Bet Online)
This is an extremely tough game to pick, but I'm going with New England.
Who wins with the spread?
The 49ers have the No. 2 total defense in the NFL, but I don't think Colin Kaepernick has what it takes to keep up with Tom Brady and the Patriots' offense.
New England held the Texans' D in check and I expect it to do the same against San Francisco.
I like the Patriots.
Over/Under: 46.5 (Bet Online)
Despite San Francisco's stellar defense, I'm taking the over.
According to Bovada, the point total has gone over in 10 of New England's last 11 games and in four of San Francisco's last five games.
With a potent offense like the Patriots, I have to take the over in this matchup.
Key Injuries (via USA Today)
WR Mario Manningham—Shoulder—QST
CB Aqib Talib—Hip—QST
Fantasy Big Plays
49ers: Frank Gore
New England is solid against the rush, but Frank Gore should be effective on the ground and through the air.
Gore hasn't rushed for 100 yards since Week 7, but he has consecutive games with touchdowns and is already over the 1,000-yard mark for the sixth time in his career.
The Patriots' defense has allowed 10 rushing touchdowns, so there's definitely hope for Gore on Sunday night.
Patriots: Wes Welker
The 49ers' defense isn't going to give up a lot of big plays on the ground or through the air, so I think it's going to be a Wes Welker-type game.
By that, I mean Brady will be looking Welker's way often on short curl and slant routes.
Closing in on another 100-catch season, Welker should see the most targets from Brady against a staunch San Francisco defense.
Key to 49ers Win: Attack Through the Air
New England's defense ranks No. 29 against the pass, meaning Kaepernick and his receivers will be the key to a 49ers win.
Allowing 22 receiving touchdowns this year, the Pats' defense is definitely susceptible through the air.
Look for Vernon Davis and Michael Crabtree to see a lot of targets from Kaepernick, who needs to have a huge day for San Francisco to win on the road.
Key to Patriots Win: Get After Kaepernick
When the St. Louis Rams defeated Kaepernick and the 49ers, they got pressure on the young QB, to the tune of three sacks and five quarterback hits.
I think putting pressure upon the inexperienced QB is New England's best bet on Sunday night.
The Patriots have 28 sacks on the season and will need to increase that total if they're going to take down the 49ers.
Prediction: 49ers 20, Patriots 28
San Francisco's defense doesn't hold up in this one, as Brady and the Pats' offense is too much to handle.
I think Brady continues his MVP-like run with three touchdowns as the Patriots further their case for a first-round bye.
Follow me on Twitter: Follow @Pete_Schauer