Del Potro, once ranked among the Top 5 players in the world, improved his record this season to 18-5 with a 6-4, 6-4 win over Ricardo Mello of Brazil.
The Argentine, who won the U.S. Open title in 2009 and captured the Delray Beach Championships in February, advances to a second-round match against the No. 29 seed, Phillip Kohlschreiber of Germany.
In other first-round action Wednesday, Xavier Malisse of Belgium eliminated American Ryan Sweeting 7-6 (7-3), 6-4 and Paolo Lorenzi of Italy beat Ivan Ljubicic of Croatia 7-6 (9-6), 6-1.
South African Kevin Anderson dropped Russian Nikolay Davydenko 6-4, 6-3, and Alex Bogomolov Jr. of the United States advanced to a second-round match with Andy Murray by beating Romanian Victor Hanescu 6-3, 4-6, 7-5.
Marcel Granollers, Pablo Andujar, Julien Benneteau, Somdev Devvarman, Ivan Dodig, Marsel Ilhan and Mikhail Kukushkin won their first-round matches.
The 32 seeded players -- including Murray, Rafael Nadal, Novak Djokovic, Roger Federer, Andy Roddick and Robin Soderling -- received first-round byes.