Philadelphia won the first three on this six-game road trip, scoring four goals in each victory but was stymied by strong goaltending by Colorado.
"Sometimes you run into a hot goalie you can't do anything about," forward Scott Hartnell said.
The Flyers tried, generating several chances in the final minutes only to be denied. Varlamov had several good stops throughout the game, including one on Hartnell with 3:24 left.
It was the second time Varlamov made a big save on the big forward.
Mason came off for an extra skater with 1:29 left and Philadelphia had several chances but couldn't get the equalizer against Varlamov.
"It seems that's the story every night," McGinn said. "We let him do his thing and we've got to put enough in because we know he's going to give his best."
Although Varlamov started his career in the Eastern Conference, he only faced Philadelphia twice before Thursday. He played as if he knew them well, sliding side-to-side to make big saves.
Down 1-0, the Flyers had a great chance to tie it on a power play in the first. Steve Downie got behind the Avalanche defense and broke in alone on Varlamov, but the goalie made a pad save to preserve the lead.
Varlamov denied Hartnell on a chance early in the second, and then laid out to deny Downie again on a power play with 12:54 left in the middle period.
"Downie almost got me with the backhand," Varlamov said. "He has great skill. I was lucky on that one."
Two minutes later, O'Reilly made it 2-0 when his shot went off Mason and over his head into the net. It was his 14th of the season.
"It hit me on the top of the right pad, I just bent down and it went over," Mason said.
The Flyers broke through when Simmonds slid across the front of the crease and tipped in a shot from defenseman Andrej Meszaros with 6:12 left in the second. It was Simmonds' 13th goal of the season.
But that was all they could get against Varlamov. They had just three shots through the first 14:30 of the third before putting seven shots on net the rest of the way.
Each time, Varlamov was there to make the save.
"The first two shifts (of the third) they were in our zone but we weathered that storm and went after them," Hartnell said. "A lot of pucks on net, we were screening goals, peopled driving the net. You do that most games you get rewarded but tonight we got stoned."
Colorado took a 1-0 lead midway through the first when McGinn, trailing the play after a Philadelphia turnover, scored off Matt Duchene's rebound. It was McGinn's eighth of the season and second in as many games.
"They did a good job of driving the net," Colorado coach Patrick Roy said of Duchene and McGinn.
The Flyers played most of the game without forward Michael Raffl. Raffl suffered a concussion when he was checked into the boards by Gabriel Landeskog early in the second period.
"I didn't think it was a penalty," Flyers coach Craig Berube said. "He's against the glass, he hit him, it's tough play. I didn't think it was a dirty hit at all."
Landeskog extended his points streak to five games with his assist on O'Reilly's goal. ... Colorado has won six straight home games against the Flyers. ... Colorado D Ryan Wilson was a late scratch from the lineup. ... Philadelphia C Vincent Lecavalier needs eight goals to reach 400 for his career. ... Avalanche C Paul Stastny was selected to the U.S. Olympic team Wednesday.
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