Hoping to build on the momentum of their comeback win at Miami, the Broncos donned their alternate orange jerseys and returned home for an interconference duel with the Detroit Lions. The Broncos grabbed the early lead in the first quarter, with a 39-yard field goal by placekicker Matt Prater. However, the Lions would dominate the remainder of the game, beginning with a 41-yard touchdown pass from quarterback Matthew Stafford to wide receiver Titus Young, followed in the second quarter by a 50-yard field goal by placekicker Jason Hanson, a 1-yard touchdown pass from Stafford to tight end Tony Scheffler and a 1-yard touchdown run from running back Maurice Morris, giving Detroit a 24-3 halftime lead. The Lions continued their domination in the third quarter, with a 24-yard fumble return for a touchdown by defensive end Cliff Avril, a 56-yard touchdown pass from Stafford to wide receiver Calvin Johnson, followed in the fourth quarter by cornerback Chris Houston returning an interception off Broncos' quarterback Tim Tebow 100 yards for a touchdown. The Broncos finally got into the end zone, with Tebow throwing a 14-yard touchdown pass to wide receiver Eric Decker, but the outcome of the game had already been decided in Detroit's favor.

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