Champion Andy Roddick retired hurt from his Nasdaq-100 Open second-round match against Spain's Fernando Verdasco because of a wrist injury on Friday.
Serena Williams, holder of the women's title, fared better than Roddick, crushing Russia's Vera Douchevina 6-3, 6-0 to earn a third-round clash with Israel's Shahar Peer.
Eighth seed Venus Williams routed Germany's Anna-Lena Groenefeld 6-2, 6-0 while second seed Maria Sharapova swept past Greek Eleni Daniilidou 6-0, 6-4.
Former world number one Justine Henin-Hardenne celebrated her first match since last year's U.S. Open by overcoming American Abigail Spears 6-4, 6-3. The Belgian was laid low by a debilitating virus for much of 2004.
Roddick's hopes of retaining his title ended prematurely, with Verdasco leading 7-6, 4-3, after on-court treatment failed to solve the problems with the American's right wrist.
"I've got a light sprain on my wrist," a downcast Roddick told reporters.
"At 5-5 in the first set he hit a return real quick and I hit something the wrong way. It was tough for me to hit serves out there once it had happened."
Verdasco, who narrowly lost to Roddick at the Pacific Life Open last week, took the first set after the second seed twice double-faulted in the tiebreak, once on set point in his favour and again when he was set point down.
TOUR TRAINER
Roddick showed his frustration by slamming his racket on
The strapping Bastholt put on Roddick's wrist did little to help and he retired after one hour 15 minutes.
"I'm just disappointed. You try to have as positive an outlook as you can and I'm glad that they don't think there is any permanent damage," said Roddick.
His elimination means world number three Roddick will drop the ranking points he earned by winning the title last year and thereby lose ground on number two Lleyton Hewitt, who pulled out through injury before the tournament began.
Marat Safin, the world number four, will overtake Roddick if he keeps winning his matches in Miami. He kept up the pressure on the American, even though he had to fight hard to put out Georgia's Irakli Labadze.
The Russian eventually won 6-4, 2-6, 7-6 in a match that lasted two and a half hours.
Fifth seed Carlos Moya saved three match points to edge American James Blake 4-6, 7-5, 7-6.
Moya's fellow Spaniard, 12th seed Tommy Robredo, pulled out with a shoulder injury, handing his third-round opponent Jiri Novak a walkover into the last 16.
Xavier Malisse was leading 6-3, 5-5 when he was defaulted from his match against Spain's David Ferrer for unsportsmanlike conduct. Umpire Cedric Maurier ruled that the Belgian had made a profane remark.