Thanks to the four-hit pitching of Mark Buehrle and an array of timely contributions, the White Sox held on for a 5-3 victory and snapped left-hander Jon Lester's seven-game winning streak.
The victory kept the White Sox in first place in the American League Central.
"All of last year was so miserable that [blowout losses] happened a lot more than everyone thinks," said Buehrle, who snapped a two-game losing streak. "Just to go out there and playing the world champs and getting the first win is huge, to get that confidence."
Buehrle (9-10) effectively changed speeds to equal his season high with eight strikeouts. He allowed only one runner to reach second base through the first seven innings.
"They don't go after pitcher's pitches," Buehrle said. "So to shut this lineup down, it's different without [the traded Manny Ramirez], but it's one of the best in the league."
Buehrle was pulled after allowing a single to Kevin Youkilis to start the eighth, and Boston cut the lead to 4-3 on Dustin Pedroia's three-run homer off Octavio Dotel that extended his road hitting streak to 27 games.
But Carlos Quentin provided insurance with his league-leading 31st home run in the eighth.
"The bottom line is we have to take care of our own business, and we have to win games," A.J. Pierzynski said.
The White Sox seemed well-prepared for Boston, as advance scout Bryan Little watched the Red Sox eight times recently.
Offensively, the White Sox put together one of their finest games. Orlando Cabrera, who helped Boston win the 2004 World Series, perfectly executed a hit-and-run play that set up the White Sox's first run in the third off Lester (10-4).
In the fifth, Juan Uribe executed a sacrifice bunt that moved two runners into scoring position. Uribe received an ovation from several thousand fans after laying down the White Sox's 20th sacrifice bunt of the season. The White Sox had 41 bunts last season.
Cabrera came through again with a two-run double down the right-field line for a 3-0 lead.
The White Sox scored what proved to be the winning run in the seventh when Pierzynski ripped a drive off the right-field fence but got caught in a rundown. He stayed in the rundown long enough to allow Cabrera to score before he was tagged for the final out.
Guillen, however, wasn't that impressed.
"I think A.J. didn't hustle out of the [batter's box]," Guillen said. "He hit a ball and thought it was out, and a bad play turned out to be a great play. I bet you nobody in the stands knows about it."
• After the game, reliever Ehren Wassermann was optioned to Triple-A Charlotte.