The White Sox scored on four straight doubles in the first by Willie Harris, D'Angelo Jimenez, Frank Thomas and Magglio Ordonez.
The one by Ordonez was called a ground rule double based on the belief it caromed off the top of the wall and into the stands, foul down the right field line. But replay's show the ball also hit the foul poll, which would make it a homer.
Boston starter John Burkett retired the next three batters and the 15 after that, limiting the White Sox offense to just one hit over the next 5 2/3 innings.
The 3-0 lead the Sox had was cut to 3-2 with back-to-back homers by Kevin Millar and Trot Nixon in the second, and lost in the third after two singles set up a three-run homer by Manny Ramirez.
The White Sox came within one run with a Brian Daubach home run in the eighth, but the Red Sox came right back with a two-spot off lefty Damaso Marte. One run came on a squeeze bunt by Johhny Damon.
Marte relieved Rick White who threw a scoreless inning, as did David Sanders.
Colon lasted six innings, giving up five runs on seven hits and two walks. Colon struck out nine and threw 108 pitches.
The third game of the set will be played on Wednesday night at 7:05 CT, with Esteban Loaiza going up against Tim Wakefield. The game will be televised on Fox Sports Net Chicago.
NOTE: Thomas was ejected in the seventh for arguing balls and strikes.