The NL East leaders are a season-best 40 games over .500, boasting the majors' best record at 86-46.
Lee (15-7) extended the Phillie starters' domination, coming within one out of his sixth shutout. He left with two outs and the bases loaded in the ninth. Ryan Madson retired Yonder Alonso on a foul pop for his 25th save in 27 chances.
The Phillies' second straight shutout gave them 19 this season, most in the majors.
Pence homered off left-hander Dontrelle Willis (0-4), the Reds' hard-luck starter.
Cincinnati entered the series on a hot streak, winning four straight. The Reds ran into an old problem - they can't do anything against the Phillies' pitching.
The Phillies swept them in the playoffs last season, with Roy Halladay throwing a no-hitter. Philadelphia is 20-6 against Cincinnati lately, including 6-1 this season.
Philadelphia scored in the first inning when the Reds failed to turn a double play with two runners aboard. Pence led off the sixth with his 18th homer, extending his hitting streak to seven games. Philadelphia scored another run on a forceout in the seventh. More than enough for this staff.
Lee, who celebrated his 33rd birthday on Tuesday, hasn't lost since July 25. The left-hander has given up only six earned runs in his last six starts. He's been especially tough on the road, where he hasn't allowed a run in his last 30 2-3 innings since July 19.
Lee retired the first two batters in the ninth, then gave up a double to Joey Votto, walked Jay Bruce and hit Miguel Cairo with his 117th pitch, forcing manager Charlie Manuel to go to the bullpen.
No matter how well he pitches or hits, Willis can't get a win. He gets the lowest run support among Reds starters, and the bullpen has blown save chances in three of his starts. He gave up five hits in 6 2-3 innings.
Earlier Wednesday, the Phillies made a move to strengthen their bench, acquiring outfielder John Bowker from Pittsburgh. Bowker spent most of the season in the minors, batting .306 with 15 homers.
Bowker bats left-handed and can play left field, right field and first base. He drove over from Triple-A Indianapolis to join the team for the game.
Notes: Lee was loudly booed in the fourth, when he grounded to second baseman Brandon Phillips, took a couple steps toward first, waved his right hand and headed back to the dugout. ... Reds SS Paul Janish extended his career-worst slump to 0 for 26. ... The Phillies have won all seven of their four-game series this season. They have never had a four-game sweep in Cincinnati. ... The Phillies will start RHP Vance Worley in the final game on Thursday afternoon. Worley had a no-decision in his May 24 start against the Reds, giving up three runs in five innings. The Reds will go with RHP Mike Leake, who has given up 11 runs in 14 1-3 innings of his two starts against Philadelphia. ... The Reds plan to call up seven players from the minors on Thursday, including C Devin Mesoraco, their top draft pick in 2007. It will be his major league debut.