The 49ers' fifteenth game was an NFC West rivalry rematch against the Rams at Edward Jones Dome. The 49ers struggled in the first quarter when Steven Jackson got a 1-yard TD run, followed by QB Troy Smith getting sacked in the endzone by DE James Hall for a safety. They got back in the game after Ted Ginn returned a punt 78 yards for a touchdown, but fell further behind after kicker Josh Brown nailed a 43-yard field goal. They took the lead with Smith completing a 60-yard TD pass to WR Michael Crabtree, but fell behind again as Brown got a 30-yard field goal, followed by QB Sam Bradford throwing a 3-yard TD pass to WR Laurent Robinson. The 49ers tried to cut this lead with kicker Jeff Reed making a 47-yard field goal, but the Rams pulled away with Brown hitting a 28-yard field goal. With the loss, the 49ers fell to 5-10, eliminating them from post-season contention for the eighth consecutive season. As a result of this and a sideline argument during the game, Singletary was fired as head coach later that night.

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