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The 22-year-old Argentine has played only two tournaments since having surgery last May on a wrist injury that hampered his Australian Open campaign last year, losing in the first round in both.
One of those defeats was to Lopez in Tokyo but on Monday at the Sydney Olympic centre, wildcard Del Potro got his revenge after a monumental battle with the sixth seeded Spaniard.
“We played a beautiful match, very close,” said Del Potro, who will play German Florian Mayer, a 7-5 6-0 winner over British wildcard James Ward, in the next round.
“Feliciano is a fantastic player on this kind of surface, and I played good tennis again. I felt good all match, and finally I won a match (after) one year.”
Del Potro, who won the 2009 U.S. Open final against Roger Federer, showed great determination after trailing by a set and again in the second set tiebreak.
The third set was just as close and Del Potro was forced to save six break points before appropriately clinching victory with one of his savage flat forehands.
Ranked fifth in the world before his injury, Del Potro said he was a long way from his best and needed a lot more playing time to get back to that level.
“I need work to keep going in this road,” he said. “You know, it’s a long road to be in the top 10 again, but I’m ready to try.
“I feel happy for my victory, for everything ... I really like this life, you know. If you can play without pain, it’s much better.”
Earlier, defending champion and second seed Marcos Baghdatis pulled out of the tournament with a groin strain.
The Cypriot, beaten finalist at the 2006 Australian Open, said he did not want to risk worsening the problem before the first grand slam of the year, which starts next Monday.
“I’m a bit disappointed,” said the world number 21. “I’m the defending champion here and I wanted to play so much... It was not an easy one, but sometimes you have to take decisions that are not easy.”
In the women’s draw, local grand slam hopeful Sam Stosur delighted the centre court crowd by downing Yanina Wickmayer of Belgium 7-5 6-4.
The world number six, a French Open finalist last year, will meet twice grand slam champion Svetlana Kuznetsova in the second round.
“There’s not too many rewards when you get through matches in these kinds of tournaments,” Stosur said.
“Everyone is pretty tough ... We’ve played each other plenty of times, and I’ve had wins and losses. Hopefully tomorrow I can play like I did today, and hopefully it’ll be a good one for me.”
Two other women’s seeds had more disappointing days, fifth seed Francesca Schiavone losing 6-7 6-1 6-2 to Russian Alisa Kleybanova and sixth seed Jelena Jankovic also beaten in three sets, 7-5 2-6 6-3 by France’s Aravene Rezai.
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