If Humber harbored any dreams of back-to-back perfect outings they were squashed quickly as the right-hander walked Mike Aviles to open the game before serving up a one-out single to Dustin Pedroia and an RBI double to Adrian Gonzalez.
David Ortiz singled to left centre to push across another run and give Boston the early 2-0 lead.
Chicago pulled a run back in the bottom of the first but the Red Sox answered with a five-run burst in the third, Youkilis doing the major damage by taking a Humber pitch over the wall in right for his second career grand slam.
Jarrod Saltalamacchia cracked a solo homer to extend the lead to 7-1 in the third and also had a two-run blast in the fifth.
Boston's Felix Doubront (1-0) took the win, yielding three runs on five hits in six solid innings.
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