World number one Lindsay Davenport and Russian Maria Sharapova withdrew from the Advanta Championships in Philadelphia due to injuries and illness on Tuesday.
The loss of the top two seeds was another huge blow to the tournament, which has already seen the withdrawal of Venus and Serena Williams.
American Davenport was forced out of the $585,000 indoor event with flu while world number three Sharapova suffered a thumb injury in training, leaving defending champion Amelie Mauresmo as the top seed left in the event.
"I am extremely disappointed to have to withdraw from the Advanta Championships because of a right thumb sprain," Sharapova said on the WTA website.
"I was hoping that it would be better by now but unfortunately I am not yet able to play."
Davenport and Sharapova indicated they expect to be fit for the season-ending WTA Tour Championships,
"I am looking forward to getting healthy and defending my year-end number one ranking at the WTA Tour Championships," said Davenport in a statement.
The absence of Davenport and Sharapova cleared two major hurdles from Mauresmo's path as she chases a third straight Advanta title.
After a first round bye the Frenchwoman opens her account against Japan's Ai Sugiyama, who advanced on Tuesday with a 7-5, 6-4 win over Czech Iveta Benesova.
In other first round matches, Sesil Karatantcheva of Bulgaria upset ninth seed Vera Zvonareva of Russia 7-5, 6-3 while Martina Sucha of Slovakia needed three sets to tame France's Stephanie Foretz 6-1, 5-7, 6-1.
Seventh-seeded 16-year-old Nicole Vaidisova of the Czech Republic continued her impressive form by crushing German qualifier Vanessa Henke 6-1, 6-1 for her 16th straight win.