Josh Fields hit two homers and Jim Thome added the 503rd of his career to lift the Chicago White Sox to a 6-4 victory over the Minnesota Twins on Friday night.
Santana (15-13) struck out 11, but gave up six runs and eight hits in seven innings to lose for the fourth time in five starts. The three homers pushed his total for the season to 33, most in the American League.
Thome just missed hitting No. 504 in the seventh inning when Lew Ford leaped at the left field wall and brought the ball back
Mark Buehrle (10-9) went six innings for his first victory in eight starts.
Santana's first-inning problems continued Friday night when Fields hit a 420-foot home run to straightaway center. The reigning AL Cy Young winner has given up 13 first-inning runs, including five homers, in his last six starts.
After the Twins scored three runs in the third, Jermaine Dye had an RBI double in the fourth and Thome added a three-run shot in the fifth to give the White Sox a 5-3 lead.
Nick Punto's RBI triple in the sixth cut the lead to 5-4, but with runners on the corners and two outs, rookie Alexi Casilla inexplicably laid down a bunt and was thrown out by catcher Toby Hall to end the inning.
Fields got his second career multihomer game when he went deep in the seventh. His 22 homers are tops among AL rookies.
Buehrle, who was 0-3 with a 5.27 ERA in his previous seven starts, gave up four runs and nine hits for his first victory since Aug. 3 at Detroit.
Bobby Jenks worked a perfect ninth for his 39th save in 45 opportunities.
When the scheduled was released, it looked like this would be a pivotal series in the AL Central race.