Hoping to rebound from their first loss of the season, the Titans flew to Ford Field for a Week 13 Thanksgiving game against the winless Detroit Lions. In the first quarter, Tennessee drew first blood as rookie RB Chris Johnson got a 6-yard TD run. The Lions would respond with kicker Jason Hanson getting a 53-yard field goal. The Titans would answer with Johnson getting a 58-yard TD run, along with DE Dave Ball returning an interception 15 yards for a touchdown. In the second quarter, Tennessee increased their lead with RB LenDale White getting a 6-yard and a 2-yard TD run. Detroit would reply with QB Daunte Culpepper completing a 2-yard TD pass to TE Michael Gaines. In the third quarter, kicker Rob Bironas would kick field goals of 41 and 49 yards to put the Titans up by 31, and in the fourth quarter, he would nail field goals of 45 and 43 yards to put the Titans up for good. With the win, Tennessee not only improved to 11-1 on the season, but the Titans were the only AFC South team to defeat all four NFC North teams in interconference play. Center Kevin Mawae, DT Albert Haynesworth, and Running Backs Johnson & White were given CBS's All-Iron Award for their performance.

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