Williams, a five-time winner of the hard-court event, is out because of the left knee injury that has sidelined the American since her Australian Open title.
Del Potro has a right wrist injury that has bothered him since the start of the season.
Story continues below ↓advertisement | your ad hereThe tournament announced their withdrawals Friday, two days after saying Maria Sharapova wouldn't participate because of a bone bruise in her right elbow. Second-ranked Dinara Safina and 2008 champion Nikolay Davydenko also withdrew.
The 13-day tournament begins Tuesday. The field still includes Roger Federer, Rafael Nadal and Venus Williams.
© 2010 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.Sharapova withdraws from Key BiscayneInjury boost for Barca