Seppi, of Italy, withdrew during the first set due to an injured right foot, allowing Del Potro to grab a 4-1 victory on the hardcourts at the Lindner Family Tennis Center.
The Argentine earned a second-round date with Roger Federer. Del Potro ousted Federer in the 2009 U.S. Open final.
The top seeds here are also the top players in the world -- Novak Djokovic, Rafael Nadal, Federer and Andy Murray. Federer titled here for a fourth time by edging out American Mardy Fish in last year's final. Djokovic was the runner-up here in 2008 and 2009. Murray beat Djokovic in the '08 Cincy final.
Nine of the last 10 champions here have held the No. 1 ranking during their careers.
This is the final Masters event before the U.S. Open, which will commence August 29 in New York.
This week's winner will collect $496,000.