Jonathan Crompton threw two touchdowns, Montario Hardesty ran for two more and Rico McCoy forced two fumbles as coach Lane Kiffin grabbed his first win over a ranked opponent.
After warming up in their traditional orange home jerseys, the Vols (4-4, 2-3 Southeastern Conference) seemed to take the Gamecocks by surprise as they took the field in Halloween-inspired uniforms.
And how's this for a twist: Tennessee's victory helped Florida. The Gators clinched the SEC West when the Vols beat South Carolina.
South Carolina (6-3, 3-3) fumbled on its first two drives on a rainy night, having entered the game with only five for the season. Tennessee, hampered by turnovers early in the season, did not give the ball away for the first time this season.
The Gamecocks began clicking on offense in the second half as the Vols sputtered. Stephen Garcia connected with Moe Brown on a 31-yard touchdown pass to cut the margin to 28-13 with 2:05 left in the third quarter, but it was too little too late.
South Carolina outgained Tennessee on offense 365 yards to 341 and had four more first downs. Garcia completed 25 of 50 for 300 yards and an interception.
Justice Cunningham coughed up the first fumble on the third play of the game, and 42 seconds later Crompton hit Austin Johnson on a 38-yard touchdown toss. Crompton completed 12 of 24 for 142 yards.
On the second play of the following drive, Kenny Miles lost the first fumble of his career, and Tennessee answered with a 14-yard run by Hardesty, who finished with 121 yards rushing.
Even when they weren't fumbling, the Gamecocks couldn't find much offense in the first half. They first made it to Tennessee territory with 9:29 left in the second quarter but stalled at the Vols 47.
An illegal block by D.J. Swearinger cost South Carolina a would-be 73-yard punt return for a touchdown by Stephon Gilmore.
The Gamecocks drove 55 yards before halftime, but on third-and-3 at the Tennessee 25, Willie Bohannon dropped Miles for a 5-yard loss. Spencer Lanning kicked a career-long 47-yard field goal to cut the margin to 21-3 at the half.
Tennessee's woes on special teams continued. With Daniel Lincoln sidelined by a quadriceps injury, Chad Cunningham took over field goal duties. Lincoln had two field goals blocked in a 12-10 loss last week at Alabama, including what would have been a game-winning 44-yard shot at the end of the game.
Devin Taylor blocked Cunningham's first attempt, a 40-yarder in the first quarter. His second attempt, a 39-yarder with 4:23 left in the game, was good and drew a huge cheer from what was left of the Tennessee crowd.
Up 14-0 early in the second quarter, Kiffin opted to go for it on fourth-and-goal at the 2-yard line rather than attempt a field goal. Crompton found Kevin Cooper, who stumbled into the corner of the end zone.
The last time the Gamecocks were ranked as high as No. 21 was before the 2007 Tennessee game, when they were ranked No. 15. South Carolina - which has never won consecutive games in the Tennessee series and only won in Knoxville once - lost that game in overtime 27-24.
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