Kevin Youkilis hit a three-run home run as Chicago topped Boston, 7-5, in the second of a four-game series from Fenway Park.
The two-time World Series winner with the BoSox, who was dealt to the AL Central club on June 24, also scored twice. He had been denied victory in his Boston return in the series opener on Monday.
Alejandro De Aza knocked in a pair, while Paul Konerko and Alex Rios donated two hits and an RBI each for the White Sox, winners in seven of their last 10.
Activated from the 15-day disabled list prior to the game, Philip Humber (4-4) allowed six hits and two runs over six innings. The right-hander picked up his first win since June 16, the day before he was sidelined with a right elbow issue.
"Against a guy like (Jon) Lester, we knew there were going to be some tough at-bats," Humber said. "We grinded out at-bats and then Youkilis came up with a big hit there."
Kelly Shoppach hit a late pinch-hit, two run homer for the Red Sox, who had won two in a row. Carl Crawford added three hits, two runs scored and an RBI in defeat.
Lester (5-7) departed after just four frames, charged with seven hits and six runs.
"It keeps adding on and I'm getting tired of it," Lester said of his struggles. "I try to make adjustments, try to do the things I need to do, I'm just not getting results."
Alexei Ramirez led off with a double and scored in the sixth with help from a De Aza single to boost the Chicago lead to 7-2, but the Red Sox climbed back in with three in the home eighth.
Matt Thornton fell victim to Will Middlebrooks' base hit to plate Crawford and Shoppach's pinch-hit, two-run shot, which made it a two-run game.
Addison Reed held the fort in the ninth, earning his 15th save by retiring the side in order.
The visitors picked up two in their first at-bat on a Konerko double and Rios single, but the hosts responded in their turn with RBI singles from Crawford and Adrian Gonzalez.
De Aza doubled home Ramirez in the second to put the ChiSox back on top, then Youkilis cleared the Green Monster with two down in the fourth to make it 6-2.
Dayan Viciedo began the frame with a ground-rule double and Gordon Beckham walked with one out prior to the blast -- Youkilis' first here for a team other than the Red Sox.
Chicago, which saw its seven-game win streak at Fenway snapped on Monday, have won eight of nine in Boston since August of 2009...White Sox designated hitter Adam Dunn swiped his first base since August 16, 2008 at Houston while he played for Arizona...The White Sox placed pitcher Gavin Floyd on the DL to open up a spot for Humber...Red Sox designated hitter David Ortiz is expected to miss at least one week with an injury to his right Achilles tendon, the club said before the game...Lester, who fanned four, is now eight strikeouts away from 1,000 with the Red Sox, something only seven hurlers previously have accomplished.