Nadal lost in last year's Miami final to Nikolay Davydenko of Russia 6-4, 6-2. The Spaniard has never won Miami, also finishing as a finalist in 2005 when he lost to the world number two Roger Federer of Switzerland in five sets.
Williams is seeking her third straight Miami title after taking the title in 2007 and 2008. Williams also was victorious in Miami in 2002, 2003 and 2004 for an overall 48-5 career Miami record.
The American has lost to only three players ever at Miami, all of which are former WTA Tour number ones: Martina Hingis of Switzerland in 1998, Venus Williams of the USA in 1999 and 2005, and Jennifer Capriati of the USA in 2000 and 2001.
Williams is seeded in the singles draw to meet her sister Venus in the semifinals after the third seed, Jelena Jankovic of Serbia was upset also Saturday in the second round by Gisela Dulko of Argentina 6-4, 7-6(7-5).
In other second round play, Venus, seeded fifth, defeated Sharhar Peer of Israel 6-3, 6-3 before falling behind 0-3 in set one.
“I haven't played in almost four weeks, so just a little bit of a slow start,” Venus said. “But I always felt confident.”
Venus, the reigning Wimbledon champion, won the Miami title in 1998, 1999 and 2001.
Either Williams sister could meet the fourth seeded Elena Dementieva of Russia or the second seeded Dinara Safina also of Russia in the final.
Nadal could face the fourth seed Andy Murray of Britain in the semifinals. Murray Saturday defeated Juan Monaco of Argentina 4-6, 6-3, 6-2.
In the final, Nadal could face the second seeded Federer or the third seeded Novak Djokovic of Serbia.
Both Williams sisters as well as Federer and the fifth seeded American Andy Roddick headline Sunday's order of play at Miami.