Jose Quintana failed to allow a hit for 6 1/3 innings and Jeff Keppinger hit a go-ahead two-run homer in the fifth to help send Chicago past Boston, 3-1, in the middle test of a three-game series.
Quintana (3-1) walked only two batters heading into the seventh, until a one- out base hit from David Ortiz ended his bid for immortality. Mike Napoli and Daniel Nava added base hits of their own, chasing the left-hander from the game.
"He was making a bunch of good pitches out there tonight and that was the difference in the game," said Ortiz about Quintana.
He ended up allowing three hits and fanning five for the win. Addison Reed tossed a scoreless ninth to earn his 16th save.
Alex Rios added a late RBI double for the White Sox, who have take the first two in the set and six of eight overall.
"The starting pitching has been really good and has been able to keep us in it pretty much every game," said Rios. "Now we seem to be getting those big two- out hits and have things rolling here."
Dustin Pedroia knocked in the lone run for the Red Sox, who had swept Minnesota over the weekend.
Felix Doubront (3-2) gave up five hits and a pair of runs over six solid innings.
Quintana left with the bases loaded in the seventh, but Jesse Crain defused the situation by striking out Will Middlebrooks and Stephen Drew swinging.
Matt Thornton walked Jarrod Saltalamacchia and gave up a single to Jacoby Ellsbury to begin the eighth before giving way to Matt Lindstrom, who uncorked a wild pitch to move both runners into scoring position. Pedroia was credited with an RBI when Alexei Ramirez couldn't field his grounder cleanly, but Ortiz grounded into a double play to keep it a 2-1 game.
Ramirez atoned in the home half, hitting a one-out single and then scoring on a Rios double for a two-run Chicago edge.
Reed closed out the contest by retiring the side in order.
Chicago snapped the scoreless deadlock in the home fifth, as Dayan Viciedo singled with two down and Keppinger followed with a two-run shot to left.
Quintana walked Nava in the second and Ellsbury in the sixth while setting down the BoSox in the first, third, fourth and fifth frames.
Chicago announced that Chris Sale will not start in Wednesday's series finale due to tendinitis in his left shoulder, with Hector Santiago scheduled to take the hill in his place ... Red Sox outfielder Shane Victorino was absent due to tightness in his left hamstring ... Keppinger's homer was his first since Sept. 29, 2012 against Tampa Bay.