The Patriots began their regular season at home against the Chiefs. On the first drive of the game, a running-into-the-kicker penalty committed by the Chiefs on a fourth-down punt gave the Patriots a fresh set of downs, but three plays later, wide receiver Wes Welker fumbled after catching a pass from quarterback Tom Brady. The Chiefs recovered and started their next drive at their own 48-yard line but failed to convert on third down and punted. On the ensuing Patriots possession, the Chiefs again recovered a fumble by a Patriots receiver after a catch; this time wide receiver Randy Moss lost the ball after a 28-yard completion from Brady. After the throw, Brady was hit in his lower left leg by Chiefs safety Bernard Pollard, left the game, did not return, and was later placed on injured reserve with a torn ACL and a torn MCL. Quarterback Matt Cassel replaced Brady for the Patriots' next drive, which began from the Patriots' 2-yard line. Seven plays after a 51-yard completion to Moss from inside the Patriots' 1, Cassel hit Moss in the end zone from 10 yards out for a touchdown, giving the Patriots a 7-0 lead early in the second quarter. The teams then exchanged three-and-outs twice, before the Chiefs ended a 13-play, 51-yard drive with a 40-yard Nick Novak field goal to cut the Patriots' lead to 7-3 at the end of the first half. After a Chiefs punt on a drive in which Chiefs quarterback Brodie Croyle was injured on a sack by Adalius Thomas, the Patriots drove 80 yards on 11 plays, capping off the series with a 5-yard touchdown run by running back Sammy Morris to extend the Patriots' lead to 14-3. The next Chiefs drive began with backup quarterback Damon Huard replacing Croyle. The Chiefs drove 63 yards and trimmed the Patriots' lead to 14-10 on a 13-yard touchdown reception by wide receiver Dwayne Bowe. After three punts, Huard and the Chiefs began a fourth-quarter drive by throwing an interception to Patriots cornerback Ellis Hobbs; a 15-yard unnecessary roughness penalty on the Patriots caused their ensuing series to begin at their own 47-yard line. A handful of Morris runs and Cassel passes, including an 11-yard reception by Morris, brought the Patriots into the Chiefs' red zone, but the Patriots failed to convert on third down and settled for a 37-yard Stephen Gostkowski field goal to make their lead 17-10. Starting from his own 22-yard line with 2:20 remaining, Huard was strip-sacked on the third play of the series, but recovered his own fumble at the Chiefs' 27-yard line. On the next play, Huard hit wide receiver Devard Darling for a 68-yard completion, giving the Chiefs first-and-goal from the Patriots' 5-yard line with 53 seconds left. However, the Patriots' defense prevented the Chiefs from advancing another yard, as an incomplete pass, a Larry Johnson run for no gain, and two more incomplete passes gave the Patriots the ball back to seal their first victory of the season, and their 20th consecutive regular-season win.

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