On September 7, 2008, Romo led the Cowboys to a 28-10 win over the Cleveland Browns in their season opener. Romo completed 24 of his 32 passes for a total of 320 yards and one touchdown. After the game, Romo required 13 stitches for a large gash on his chin that occurred during the third quarter when linebacker Willie McGinest hit him in the chin with his helmet. The NFL fined McGinest $7,500 for the hit. On September 15, Romo led the Dallas Cowboys to a 41-37 win against the Philadelphia Eagles in the second game of the 2008 season. Romo completed 21 of his 30 passes for a total of 312 yards and three touchdowns. The 54 combined points scored by the Cowboys and Eagles in the first half were the second most points scored in a half during a Monday Night Football game. Romo and the Cowboys won their third straight before losing to the Washington Redskins, falling to 3-1. Following a win against the Cincinnati Bengals, Romo was injured in a loss to the Arizona Cardinals. The Cowboys, under Brad Johnson, went 1-2 the next three games, falling to the St. Louis Rams, beating the Tampa Bay Buccaneers, and losing to the New York Giants. In what became a de facto third playoff game for Romo shortly prior to its start, on December 28, Romo and the Cowboys failed to compete against the Philadelphia Eagles in a 44-6 loss. Romo committed three turnovers in the game and went 21/39 for 183 yards and no touchdowns. The loss dropped Romo's combined record in December to 5-8 and again raised questions about his performance in games of consequence.

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After the game, Romo required 13 stitches