Coming off a primetime victory over Cincinnati, the Colts flew to Reliant Stadium for an AFC South rematch with the Houston Texans. Heading into this game, Indianapolis had never lost a game to the Texans, winning their first 9 games against them. In the first quarter, the Colts got an early shock as RB Ron Dayne ran for a 3-yard touchdown and a 6-yard touchdown run.  Indianapolis would respond with 37-yard touchdown pass from QB Peyton Manning to WR Marvin Harrison. In the second quarter, the Colts tied the game with Manning completing a 9-yard touchdown pass to WR Aaron Moorehead. However, Houston reclaimed its lead with QB David Carr's 3-yard touchdown pass to RB Vonta Leach. In the third quarter, Indianapolis crept closer with K Adam Vinatieri making a 33-yard field goal for the only score of the period. In the fourth quarter, the Texans responded with kicker Kris Brown's 42-yard field goal. Afterwards, the Colts tied the game with Manning hooking up with Harrison again on a 7-yard touchdown pass, Harrison's second of the game. However, Houston managed to pull off a huge upset with Kris Brown's game-winning 48-yard field goal as time expired, giving Indianapolis their first ever loss against them. With the loss, the Colts fell to 11-4. Colts QB Peyton Manning finished the game 21 of 27 for 205 yards passing with three touchdowns and Texans QB David Carr finished with 163 passing yards on completing 16 of 23 passes with one touchdown. Rookie RB Joseph Addai ran the ball 15 times for 100 yards and former Heisman Trophy winner Ron Dayne finished the game with 153 rushing yards on 32 carries. After this game, the Colts were now 11-4, having lost 4 of 6 after a 9-0 start and dropped to 4-4 on the road.

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