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With the temperature in the mid-60s, it was as close to comfortable as the Orioles could get at the venerable ballpark on Yawkey Way.
By the bottom of the second inning, the Orioles' advantage was cut to three runs. By the end of the fifth, Guthrie and the lead were gone.
The Red Sox, buoyed by Aubrey Huff's fielding error, tied the score with three fifth-inning runs and scored twice more in the sixth for a 10-8 victory over the Orioles before an announced 38,266, a post- World War II record at Fenway Park.
"You'd like to think that you score seven, you got your No. 1 guy going the first game of the series, maybe things are going to go your way," Orioles manager Dave Trembley said.
The loss not only marred Nick Markakis' five-RBI performance, which included a second-inning grand slam off Red Sox starter Brad Penny, but it also marked a brutal beginning to the four-game series and the continuation of the team's pitching woes that are draining the momentum from the Orioles' hot start.
The Orioles (6-4) have given up 54 runs over their past five games and nine or more in four of their past five.
Guthrie had been the one starter the Orioles could count on, but his biggest miscue was allowing Boston to get back into the game with a four-run bottom of the second after the Orioles had scored seven times in the top of the inning.
The Red Sox's four-run inning included two walks, a potential double-play ball from Jason Varitek that hit off the bag and rolled into the outfield for a single, and an RBI single by Jacoby Ellsbury that bounced off the heel of center fielder Adam Jones' glove.
"I've watched the game three times now, and I'm convinced that on another night, the way we played, it could just as easily be 8-3 after five innings," Guthrie said.
"A couple breaks did not go the Orioles' way."
Guthrie allowed eight runs (five earned) on eight hits and four walks over 4 2/3 innings.
Had Huff made the routine play on Varitek's bases-loaded grounder in the fifth, Guthrie would have escaped the inning with an 8-5 lead intact. Instead, Huff booted it to allow a run to score, and Red Sox shortstop Nick Green followed with a game-tying, two-run double over Jones' head.
"I just tanked that ball," Huff said.
"I was going to try and backhand, and it kind of checked up on me and slowed down. ... I kind of got caught in between. It's a play you got to make. I take full credit for that one."
With the score tied at 8 in the sixth, Danys Baez allowed Boston to load the bases, and Jason Bay, whose two-run homer in the second started the comeback, hit a sacrifice fly, and Mike Lowell connected for an RBI single.
Trailing by two runs, the Orioles put men on second and third in the top of the eighth, but Hideki Okajima struck out Huff.
Jonathan Papelbon pitched the ninth for his third save, striking out pinch hitter Felix Pie with Ty Wigginton on first to end it.
"If we learned anything from that Texas series, no lead is ever safe, and we have to keep chipping away," Huff said.
"It seems like we let them off the hook offensively."