Coming off their road win over the Rams, the Bills flew to the University of Phoenix Stadium for a Week 5 interconference game with the Arizona Cardinals. In the first quarter, Buffalo trailed early as Cardinals QB Kurt Warner completed a 2-yard TD pass to WR Larry Fitzgerald. In the second quarter, Arizona increased its lead as RB Tim Hightower got a 17-yard TD run. The Bills responded as QB J.P. Losman completing an 87-yard TD pass to WR Lee Evans, yet the Cardinals replied with RB Edgerrin James getting a 1-yard TD run. Buffalo answered with Losman's 1-yard TD run, yet Arizona closed out the half with kicker Neil Rackers getting a 47-yard field goal. In the third quarter, the Bills tried to catch up as kicker Rian Lindell got a 48-yard field goal, but the Cardinals answered with Warner completing a 2-yard TD pass to Fitzgerald. In the fourth quarter, Arizona pulled away as Rackers nailed a 38-yard field goal, along with Hightower getting a 2-yard TD run, With the loss, Buffalo went into their bye week at 4-1. QB Trent Edwards (3/3 for 18 yards), who originally started, was knocked out the game on the Bills' third offensive play by Cardinals safety Adrian Wilson with a concussion.

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