Boston suffered a nightmare fifth inning as Chicago came from behind to deliver a second crushing win against the Red Sox in as many nights.
Atlanta Braves' Brian Jordan leaps to catch out Adam Everett
The result was 5-4 to Chicago who need just one more win in the final three play-off fixtures to end Boston's defence of their World Series crown.
A terrible fielding error from Tony Graffanino proved costly.
Elsewhere, Houston wrapped up a 10-5 win over Atlanta and the LA Angels beat the New York Yankees 5-3.
Chicago 5-4 Boston
In the Chicago-Boston match, the Red Sox charged into an early 4-0 lead with David Wells pitching well, before giving away five runs in the fifth innings.
Aaron Rowand collected an RBI double to get them off the mark before Graffanino's brainstorm.
Juan Uribe hit a roller to the second baseman, who let the potential inning-ending double-play ball roll under his glove, leaving runners at first and third bases.
And a stunning home run from Tadahito Iguchi sent the home fans into raptures.
Houston 10-5 Atlanta
Andy Pettitte pitched seven strong innings while Morgan Ensberg also gave a fine performance for the Astros in ther opening match against Atlanta.
Ensberg opened with a run-scoring single in the first inning, adding a two-run base hit and another RBI in the seventh when the Braves trailed by a just one run.
The win was the 14th of Pettite's postseason career, tying him with John Smoltz for the Major League record.
Atlanta trailed from the fourth inning and were out of it when Houston scored five runs in the eighth.
LA Angels 5-3 NY Yankees
A tight match in Anaheim swung the way of the home side in the seventh inning when Orlando Cabrera's single against Chien-Ming Wang scored in two runners.
The score went from 2-2 to 4-2 in favour of the Angels at that point and a single home run for each side in the remainder of the match left the final score 5-3.
The Yankees had a narrow lead until the sixth innings as Wang's pitching upstaged opposite number John Lackey.
But an Alex Rodriguez error let the Angels get on equal terms before Cabrera's crucial line drive in the seventh.