"The reason Johan has a few Cy Youngs is the White Sox," manager Ozzie Guillen said of the Minnesota ace's dominance over Chicago.
Not 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.
Santana doesn't put much stock in the stat.
"Not at all," he said. "I'm just doing my job. If you look, most of those homers have been solo homers. Sometimes it's about guessing right or leaving a pitch up. But I don't really worry about it. I'd rather give up a homer than just give up hits and doubles and going crazy out there."
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.
"I wanted to get to 12 to match my career low," Buehrle deadpanned. "It's kind of embarrassing it took this long to get to 10 wins. But I'm there and hopefully I can continue."
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.
"Great stuff doesn't matter if you leave a ball out over the plate," Twins manager Ron Gardenhire said. "Tonight he just didn't locate it as well and make adjustments."
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.
"Finally we got pretty good success against him," Guillen said. "It took five years to get a game like this against him."
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.
"Against that guy, you kind of close your eyes and swing," Fields said. "Every once in a while, someone deserves to get him, as much as he dominates everyone. I was just fortunate to get him tonight."
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 schedule was released, it looked like this would be a pivotal series in the AL Central race.
But the Twins never found the same magic they used last year to rally in the final two months for their fourth division title in five seasons.
Injuries to Joe Mauer and monumental struggles on offense and in the rotation behind Santana have contributed to a tough year for the Twins, who have been out of the playoff picture since being swept by Cleveland at the end of August.
It's been even worse for the White Sox, who fell into last place when they lost to Kansas City on Thursday in what will be the first losing season on the South Side since 1999.
"That's weird," Guillen said when asked about the inconsequential nature of this series. "Two teams that were picked to finish high and we didn't. That should teach a lesson to people out there."
The lesson, Guillen said, is about the strength of the AL Central. The Indians have been strong for most of the season and Detroit was in playoff contention until being swept by Cleveland last week.
"In this division, when you go down," Guillen said, "you go down in a hurry."
Punto has had a miserable season at the plate, but he is trying to finish on a high note. He entered the game hitting .211, but extended his season-high hitting streak to seven games with a single in the fourth. ... Thome is 23rd on baseball's career home run list. Eddie Murray is 22nd with 504.