The eighth-seeded Argentine made his season debut on clay. He broke his opponent's serve in the third and seventh games to take the first set in under half an hour.
But Del Potro's double-fault in the eighth game of the second set helped Sousa, of Portugal, even the match.
Del Potro double-faulted again to lose his service in the first set of the opening game before breaking back twice. He is working his way back up the rankings after undergoing wrist surgery almost a year ago.