Lester surrendered five fifth-inning runs, punctuated by Justin Morneau's three-run homer over the right-field baggie.
"One pitch cost me three runs -- that was the ballgame right there," Lester said. "I felt like I threw the ball pretty well; made one mistake."
Manager Terry Francona agreed that Lester has been plagued in poor starts by one bad inning.
"I think for the most part, when you look back, it can come down to one pitch," Francona said. "It was almost the same thing as Seattle. He looks like he has a chance to get out of it, and then one pitch and all of a sudden there is a crooked number on the board. I know he is frustrated."
Lester had allowed only one run through five innings when he gave up four in the sixth inning against the Mariners on May 15. He surrendered six earned runs in the fifth against the Rays on May 9. He allowed all three of his runs in the fifth on May 4 against the Yankees. He suffered a five-run second inning against the A's on April 13. It was four runs in the fifth against the Rays on April 8.
Are one-inning struggles the story of the season?
"Yeah, I guess," Lester said. "I don't know what to tell you guys. I don't really have any answers for you."
The Red Sox mustered only two runs against steady Twins right-hander Nick Blackburn. Dustin Pedroia's RBI double in the fifth gave Boston a 1-0 lead.
Minnesota pecked away at Lester in the bottom half of the frame with three singles from the first four batters. Denard Span's RBI groundout gave the Twins their first lead. Joe Mauer walked next to put two runners on. Lester threw a high-and-tight 1-0 fastball that Morneau crushed for the game-changing homer.
"He was obviously looking for a fastball in and he didn't miss it," Lester said.
"He didn't get the fastball where he wanted to on Morneau, and he hit it as hard as you are going to hit it," Francona said.
After the game, Morneau agreed that it was one of the hardest home runs that he's hit.
"I hit it and went, 'I think it's gone,' and then I went, 'Uh oh, it's hooking and might hit the baggie,'" Morneau said. "I got scared for a second, and then it went over."
The fifth-inning damage could have been far more extensive, but Jacoby Ellsbury made one of the year's best catches with a sprawling, over-the-shoulder catch on a Delmon Young rocket to center field.
Boston cut the lead to 5-2 in the seventh. With runners on first and third, J.D. Drew grounded to Matt Tolbert, who flipped to a covering Nick Punto for the second out of the inning. Punto's throw to first bounced prematurely and got away from Morneau at first. Drew ran into first-base umpire Chris Guccione as he rounded the base. Morneau retrieved the ball and gunned down Drew at second.
Francona jogged from the dugout to jaw at Guccione, but he didn't do so to argue umpire interference.
"No, I just wanted to yell at him because he got in the way," Francona said. "It's just hard to watch."
David Ortiz went 1-for-3 with a double and a walk batting sixth in his first game hitting outside of the No. 3 spot in the order since May 2005.
"The biggest things for me was he didn't look frustrated," Francona said.
Blackburn went seven innings, allowing two runs -- one earned -- on eight hits and two walks. He struck out seven.
"He was very tough," Francona said.
Lester fell to 3-5 with a 6.07 ERA in a frustrating season in which he has been very good at times and seen his success crumble in short stretches.
"I feel like he is so much closer to being real good and dominant than he is to the five-run inning," Francona said.