Jack Cust hit an RBI double in the seventh to give Seattle the lead as the Mariners roughed up reliever Bobby Jenks (1-2), who was booed after allowing two runs in the inning and giving up Boston's one-run lead.
Vargas (1-2) gave up eight hits and four runs while striking out four and walking two.
Justin Smoak drove in two runs and Brandon League picked up his sixth save as the Mariners held the Red Sox hitless after the fourth inning.
Mike Cameron homered twice for the Sox, who opened their 11-game homestand by losing for the third time in their last four games.
Boston starter Daisuke Matsuzaka was pulled in the fifth inning with tightness in his right elbow. Dice-K had already thrown 81 pitches before Ichiro Suzuki led off the fifth with a single. It was the first hit Matsuzaka had allowed since the first inning, but he was spotty with his control from the start, throwing 25 pitches in the first.
Matsuzaka allowed three hits and four walks, and struck out four before he was replaced by Matt Albers, whose throwing error in the sixth allowed Suzuki to score and pull the Mariners to 4-3.
Suzuki hit another leadoff single in the seventh, Chone Figgins followed with a double and, after Milton Bradley struck out, Miguel Olivo hit an RBI grounder to score Suzuki. Cust hit a line drive that bounced off the scoreboard in left, easily scoring Figgins and putting the Mariners ahead to stay.
Cameron had put the Sox ahead 4-2 in the fourth with his second homer of the season, a towering shot over the Green Monster. His first of the season came in the second inning, a fly ball that tucked just inside the fair pole in the shallow right-field corner.
Kevin Youkilis tied it 2-all on an two-out single to right in the bottom of the third, which could have been over if not for some misfortune for the Mariners.
Darnell McDonald drew a walk in the third after appearing to strike out. He tipped what was initially called strike three and catcher Miguel Olivo appeared to catch it, but first base umpire Greg Gibson ruled the ball hit the ground – replays showed it didn't.
Jacoby Ellsbury then hit a grounder to second, but Seattle couldn't turn the double play because Adam Kennedy bobbled the ball and had to settle for tagging out McDonald. Ellsbury scored on Youkilis' hit and David Ortiz followed with another single to score Adrian Gonzalez, who also reached on a two-out single, and the Sox led 3-2.
The manual scoreboard in left field spelled out "Go Bruins" and "Go Celtics" before the game. … Struggling Red Sox LF Carl Crawford was given the night off. Crawford is batting just .160 this season and Francona thought it was a good chance to get some right-handed hitters a chance against Vargas because of a string of lefties the Sox are due to face. … Youkilis, who jammed his left hip Thursday night in Baltimore, was able to play. … Seattle 2B Jack Wilson, who left Thursday's game in Detroit with an irritated eye, did not start but came in as a defensive replacement in the eighth. … Friday marked the 25th anniversary of the night Roger Clemens struck out 20 Mariners in a game at Fenway Park.