The Giants opened the regular season against the Indianapolis Colts on Sunday night, September 10. In a highly anticipated matchup that was nicknamed "Manning Bowl I", quarterback Eli Manning had to lead his Giants against his older brother, quarterback Peyton Manning, and the Colts. The Giants fell behind early as Peyton led the Colts on a 17-play, 58-yard drive that ate up 8:53, ending with kicker Adam Vinatieri hitting a 26-yard field goal. In the second quarter, the Colts would build their lead with a 32-yard Vinatieri field goal, and after Jay Feely missed a 40-yard field goal wide left for the Giants, Peyton Manning found tight end Dallas Clark on a 2-yard touchdown pass. Down 13-0, and starting at their own 14-yard line with 2:18 to play in the half, the Giants' offense woke up, with Eli completing a 34-yard touchdown pass to wide receiver Plaxico Burress with 40 seconds to play in the half. But that was a little too much time left on the clock: The Colts would end the first half with Vinatieri kicking a 48-yard field goal. On the opening drive of the second half, the Giants continued their momentum from the first half, as Eli completed a 15-yard touchdown pass to tight end Jeremy Shockey, completing an 11-play, 69-yard drive that ate up 7:50. After the teams traded punts, Peyton Manning was intercepted by R.W. McQuarters, but Eli Manning fumbled, and the ball was recovered by Robert Mathis. On the ensuing drive, running back Dominic Rhodes scored from 1 yard out to open up a 23-14 lead with 13:21 to play. Undaunted, the Giants would then respond with a 1-yard touchdown run of their own from running back Brandon Jacobs. The Giants forced a punt on the next possession, but longtime Indianapolis punter Hunter Smith pinned the Giants at their own 7 with 4:58 to go. On that drive, Tim Carter was whistled for a questionable pass-interference call, negating a 19-yard reception for a first down. On the next play, Eli Manning was picked off by Nick Harper. Vinatieri kicked a 32-yard field goal with 1:16 to play to cap the scoring.

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