Coming off their win over the Bengals, the Colts stayed at home for their Week 15 interconference game with the winless Detroit Lions. Indianapolis delivered the game's opening hit in the first quarter as running back Dominic Rhodes got a 1-yard touchdown run. The Lions would respond with a 51-yard field goal from kicker Jason Hanson. The Colts would add onto their lead in the second quarter as rookie running back Chad Simpson got a 2-yard touchdown run, yet Detroit answered with quarterback Dan Orlovsky completing a 33-yard touchdown pass to wide receiver Calvin Johnson. Indianapolis would close out the half quarterback Peyton Manning completing a 3-yard touchdown pass to tight end Dallas Clark. The Lions would begin to catch up in the third quarter as Hanson got a 30-yard field goal. In the fourth quarter, Detroit tied the game with running back Kevin Smith getting a 1-yard touchdown run, followed by Orlovsky's 2-point conversion pass to tight end Casey FitzSimmons. The Colts would pull away with Rhodes getting another 1-yard touchdown run, followed by kicker Adam Vinatieri nailing a 31-yard field goal.

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