In 2001, Mattek again received a wildcard into the qualifying at the Ericsson Open in Key Biscayne, Florida, but lost in the second round of the qualifications to Sandra Cacic. Mattek received direct entry into the ITF event Boynton Beach due to a wildcard. She defeated top-seeded Elena Likhovtseva in the first round and Jennifer Hopkins in the second round, but lost in the quarterfinals against Åsa Carlsson. With these successes, she rose to World No. 343 in the rankings. Mattek received direct entry into the tournament at Amelia Island, Florida thanks to a wildcard. However, she lost to fellow American Jill Craybas in the first round. Mattek next played another ITF event in the Bronx as a wildcard, but lost in the first round to Sylvia Plischke. Mattek played her first main draw as a wildcard at a Grand Slam tournament at the US Open but lost to Australia's Alicia Molik in the first round. Mattek ended the year ranked world No. 338.