Hoping to snap an eight-game losing streak, the Rams stayed at home for a Week 16 NFC West rematch with the San Francisco 49ers. St. Louis would trail in the first quarter as 49ers kicker Joe Nedney got a 48-yard field goal. The Rams would take the lead in the second quarter as kicker Josh Brown got a 43-yard field goal, quarterback Marc Bulger completed a 30-yard touchdown pass to rookie wide receiver Keenan Burton, and Brown making a 38-yard field goal. After a scoreless third quarter, St. Louis added onto their lead as Brown nailed a 22-yard field goal. However, San Francisco rallied with quarterback Shaun Hill completing a 3-yard touchdown pass to former Rams wide receiver Isaac Bruce and a 48-yard touchdown pass to wide receiver Josh Morgan. With their ninth-straight loss, St. Louis fell to 2-13 and were swept by the 49ers for the first time since 2005.

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