The Argentine advanced against an injured Andreas Seppi on Sunday, setting up a second-round rematch with Roger Federer. Del Potro beat Federer in the 2009 U.S. Open final.
"If I have a good day, maybe I can make a surprise," said del Potro, currently ranked No. 19. "Not many players can beat Federer. I've already beaten him twice, so I know how to play him. But it's Roger. He's the favorite."
Play began Sunday in the men's draw at the tournament, which combines the Cincinnati Women's Open and the Cincinnati Masters for the first time.
In the evening session, James Blake advanced with a 3-6, 6-3, 6-2 victory over Marcos Baghdatis, avenging a five-set loss to him at this year's Wimbledon.
The first day also produced some star power when golfer Rory McIlroy, who competed at the PGA Championship in Atlanta earlier in the day, was spotted watching girlfriend Caroline Wozniacki's practice session on court 15.
The opening match ended when Seppi withdrew because of an injured right foot with del Potro ahead 4-1 in the first set. Del Potro is playing in Cincinnati for the first time since 2007, hoping to generate some momentum heading into the U.S. Open. He reached the round of 16 at Wimbledon this summer for the first time.
He won 17 of the 22 points in the first four games on Sunday, losing only one point off his serve.
"I felt confident in my forehand," del Potro said. "My winners I set up well. I thought my serve was good. We only played (five games) but I felt like I hit pretty well."
Seppi won his only game after a lengthy injury timeout to get treatment on his right foot. The Italian retired from the match immediately after that game.
Del Potro would have preferred more of a challenge in his opening match to get ready for Federer.
"It's not nice when the match is as short as the one today," he said. "But it happens."
Del Potro battled a wrist injury much of last year, causing him to withdraw from several matches. He underwent wrist surgery on May 4, 2010, preventing him from defending his U.S. Open title.
The wrist still bothers him a little bit, but del Potro doesn't think it will be a factor against Federer.
"When the weather is very humid I feel some pain," he said. "But I feel like I can play and have success. It's always special when you play Roger. I'll need to play almost perfect."
Blake is also hoping to build up some confidence going into the year's final Grand Slam. Sunday's win was Blake's first over Baghdatis in three meetings.
"Going into Wimbledon I hadn't felt good (physically) or played with confidence in a while," he said. "He made some unbelievable returns in the first set. But once I gained the advantage I put my foot on the accelerator without letting off."
Del Potro sets up clash with Federer in Ohio
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