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Brandon Marshall caught nine passes for 87 yards and two touchdowns in the Chicago Bears' 27-21 win over New York, sending the Giants to their first 0-6 start since 1976.
With the Giants trailing 27-21 with 5:21 left, New York got the ball at its own 15. Eli Manning drove his troops to the Chicago 36 before he tossed his NFL-leading eighth fourth-quarter interception to Tim Jennings with 1:54 remaining to seal the outcome.
"No turnovers. No sacks. It definitely helped us win," said Bears offensive guard Kyle Long.
Chicago's Marshall was limited to 161 yards and a score on 16 catches over his last three games.
The injury-riddled Giants were without running back David Wilson who suffered neck injury in their last game.
This was be the 49th regular season meeting between the Giants and Bears, with Chicago now holding a 28-19-2 advantage.
Another Super Bowl berth is likely a non-starter for New York.
Since the NFL changed to the current playoff format in 1990, no team has started 0-6 and made it to the post-season.
Quarterback Manning is the first player to throw 15 interceptions in the first six games of a season since Dan Fouts in 1986.
Filling in for Wilson, Brandon Jacobs ran for 106 yards and two scores on 22 carries in defeat.
"We're all sick of losing, but we put ourselves in this position. There is only one way to get out of it," Giants head coach Tom Coughlin said.
In other key NFL games this weekend, quarterback Tom Brady could have his favourite target back as the New England Patriots take on the unbeaten New Orleans Saints.
Tight end Rob Gronkowski is hoping to take the field for the first time this season as the Patriots try to rebound against the Saints after losing 13-6 to the Cincinnati Bengals last weekend.
New England has won its first four games despite a subpar showing so far on offence. It finally caught up to them in last weekend's loss as they scored their fewest points in a game since 2006.
Brady was limited to 197 yards on 18-of-38 throwing.
The 24-year-old Gronkowski had a terrific season in 2011, logging 1,327 receiving yards and 18 touchdowns, and had 55 catches for 790 yards last year before breaking his forearm.
He returned for the playoffs, but again broke the forearm. Gronkowski had three surgeries this past offseason.
Peyton Manning's red-hot Denver Broncos face the winless Jacksonville Jaguars in Colorado.
While the Broncos have been brilliant through a 5-0 start, the hapless Jaguars are being compared to all-time lowly squads, including their own 4-12 team of 1995.
Denver has also won 16 consecutive regular-season games, while the Jaguars have dropped 10 straight.
Dallas quarterback Tony Romo will be looking to bounce back as the Cowboys take on the Washington Redskins.
Romo and the Cowboys are coming off an emotional loss at home and face another stiff challenge Sunday against the NFC East rival Redskins.
The Cowboys came so close to upending Manning and the Broncos in last weekend's 51-48 loss, but a late interception by Romo allowed the visitors to march into scoring position and kick a game-winning field goal.
The interception by Romo, just the second of the season, was his only flaw of the game and eventually dropped the Cowboys to 2-3.
The Redskins are 0-1 in the NFC East and winless against the conference this season, while Dallas is 1-0 in the division and 2-0 in the NFC.
In other games this weekend it is, Green Bay at Baltimore, Philadelphia at Tampa Bay, Pittsburgh at NY Jets, Carolina at Minnesota, Oakland at Kansas City, St. Louis at Houston, Cincinnati at Buffalo, Detroit at Cleveland, Tennessee at Seattle and Arizona at San Francisco. The Monday night contest has Indianapolis visiting San Diego.