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 Varitek didn't start as Kevin Cash caught knuckleballing starter Tim Wakefield. But he came up with one out in the ninth and drove a 1-2 pitch from Lewis (0-1) the opposite way to left-center for his third career homer as a pinch-hitter.
Following Varitek's third homer this season, Boston loaded the bases and made it 5-3 on Kevin Youkilis' RBI single.
The Red Sox, who won three straight over the Indians to advance to the World Series last October, will take a four-game winning streak to New York for a two-game set at Yankee Stadium starting Wednesday.
David Aardsma (1-1) got the final out in the eighth and Hideki Okajima worked the ninth for his first save.
Boston rookie infielder Jed Lowrie drove in three runs in his major league debut.
Victor Martinez had three hits and two RBIs for the Indians, who have dropped five of six and lost closer Joe Borowski on Tuesday. He was placed on the 15-day disabled list with a strained triceps muscle.
One of Cleveland's many problems is a lack of hitting. The Indians came in batting a league-worst .241 as a team.
With Wakefield out, the Indians tied it 3-3 in the seventh when reliever Manny Delcarmen hit Ryan Garko with the bases loaded.
Indians starter Paul Byrd didn't allow an earned run in six innings, but the right-hander could only sit and watch in the seventh as Cleveland's bullpen failed to hold a 2-1 lead.
Jorge Julio came in and walked Boston's first two hitters before getting pulled. Rafael Perez relieved and nearly made a diving catch on Julio Lugo's bunt, but the ball bounced off his glove and caromed through catcher Martinez's legs.
Lowrie, called up from Pawtucket last week, hit a two-run single to center to make it 3-2.
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Dumfounded by Wakefield's dancing knuckleball for four innings, the Indians scored twice in the fifth to take a precarious 2-1 lead.
Casey Blake led off with bloop single and Wakefield walked Grady Sizemore. Blake moved up on David Dellucci's fly to center, and after Travis Hafner walked, Martinez singled to center to score two. Jhonny Peralta missed a chance to add runs, bouncing into a 5-4-3 double play.
An error by right fielder Franklin Gutierrez helped the Red Sox take a 1-0 lead in the fifth.
With one out, Jacoby Ellsbury singled to right and never slowed down as he rounded first. Gutierrez slightly bobbled the ball, just enough to allow the speedy Ellsbury to take second. Lugo followed with a single to move Ellsbury to third.
Lowrie then hit a hard grounder to short but was able to beat out the relay throw to first as Ellsbury scored.
Notes: Indians OF Dellucci robbed Coco Crisp with a diving catch in the sixth. Red Sox INF Alex Cora, out since April 9 with a sore right elbow, took grounders but may be headed to the DL later this week. ... Gutierrez's gaffes were not limited to the field. He got picked off second in the third inning by Wakefield, who caught him wandering off one pitch after a steal.
[Associated Press; By TOM WITHERS]
Copyright 2008 The Associated Press. All rights reserved. This
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