Williams defeated Argentina's Gisela Dulko 6-3, 6-4. Williams was the Charleston runner-up in 2003.
In other second-round action, Romanian Sorana Cirstea beat third-seeded Russian Anna Chakvetadze 6-2, 1-6, 6-2. Sixth-seeded Marion Bartoli of France survived a second-set loss to beat Australia's Casey Dellacqua 7-5, 4-6, 6-1.
Safina lost to Serbian star Jelena Jankovic in last year's finale here.
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