But fourth seed Lindsay Davenport kept up her winning streak in California, landing her 10th consecutive victory in her home state by defeating Croatian teenager Karolina Sprem 6-4, 6-0.
Playing her first match on hardcourts after reaching the Wimbledon semi-finals at the start of the month, Frenchwoman Mauresmo was overpowered by Molik, who served well and shone at the net.
"It's very disappointing," Mauresmo told reporters. "I don't have much to say about what happened.
"She played her game the way she wanted and didn't make the unforced errors that I expected."
The 23-year-old Molik avenged her defeat at the hands of Mauresmo at this year's Australian Open.
"I expected to win the match," said the world number 29. "It was a little bit of revenge because the last time we played I had the match in my hands and let go of my chances.
"I was determined that it wasn't going to happen this time."
Despite the defeat, number three Mauresmo will leapfrog number two Kim Clijsters in the world rankings on Monday. The Belgian, who reached the final here last year, has not played since April due to a wrist injury.
"I've said all along that I want to get to number one by playing well and winning big tournaments," Mauresmo said. "But if I get there another way, I'll take it."
GOOD RUN
However, world number four Anastasia Myskina and number five Davenport can both pass Mauresmo and Clijsters should they advance deep into this week's tournament.
Former number one Davenport is coming off title triumphs at nearby Stanford and Los Angeles. After a difficult first set against the hard-hitting Sprem, she ran away with the match.
The 28-year-old American controlled the contest with a variety of well-placed serves and groundstrokes that kept finding the lines.
"This has been a really good run for me," said Davenport, who now plays former Wimbledon champion Conchita Martinez.
"I have so much confidence and I'm playing the big points better. Sometimes that's all you need to carry you through certain matches.
"But I'm definitely a little tired physically and mentally so this tournament will be the toughest test for me."
Mauresmo was not the only seed to fall, as French teenager Marion Bartoli crushed number nine Paola Suarez of Argentina 6-3, 6-0.
Seventh seed Svetlana Kuznetsova of Russia beat Slovak Daniela Hantuchova 6-1, 6-2 while eighth seed Ai Sugiyama of Japan dismissed fellow countrywoman Shinobu Asagoe 6-2, 6-2.
Russia's Elena Bovina defeated Eleni Daniilidou of Greece 6-1, 6-4 to earn a third-round match against top seed Serena Williams.
Argentina's Gisela Dulko put out former French Open winner Mary Pierce 6-3, 7-6 and now takes on her former junior doubles partner, Wimbledon champion Maria Sharapova.
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