In the last interconference duel of the season, the Lions traveled to Indianapolis, Indiana to take on the Indianapolis Colts. The Colts struck first when Dominic Rhodes ran in a TD from 1 yard midway through the first quarter. The Lions responded a few minutes later with a 51-yard field goal by Jason Hanson. With just under 6 minutes left in the half, Chad Simpson of the Colts scored a TD from 2 yards. Calvin Johnson of the Lions responded a few minutes later by catching a 33-yard TD pass. The Colts struck back with just under a minute in the half, when Dallas Clark caught a 3-yard TD pass. The only points for either team in the 3rd quarter was a Jason Hanson 30-yard field goal. In the fourth quarter, Kevin Smith ran in a TD from 1 yard out. The Lions decided to go for the 2-point conversion to tie the score and were successful when Casey Fitzsimmons caught a pass for the conversion. The Colts responded with another Dominic Rhodes 1-yard TD run and put the game out of reach with a 31-yard Adam Vinatieri field goal. With the loss to the Colts, the Lions became the third team (after the 1976 Buccaneers and the 1980 Saints) to lose the first 14 games of the regular season. They were the last team to started 0-14 until the 2016 Browns did it in 2016. With their 11th straight road loss, the Lions fell to 0-14 and 0-4 against AFC Opponents.

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