The former world No. 1 Williams notched her 12th straight match victory with a 6-3, 7-6 (7-5) decision against Czech Lucie Hradecka on the hardcourts at the Lindner Family Tennis Center. Williams fired seven aces in the 1-hour, 39- minute win.
The 13-time Grand Slam champion Williams is seeking her third title in three events, having titled in Toronto last week and Stanford last month.
Next up for the American great will be Aussie Samantha Stosur, who lost to Williams in this past Sunday's finale in Toronto.
Additionally, fifth-seeded Li Na moved into the third round with a 6-3, 6-4 handling of Czech Lucie Safarova. The Chinese Li captured this year's French Open title and was January's runner-up to Clijsters at the Australian Open.
Last week's Toronto runner-up to Williams, the 10th-seeded Stosur, reached the second round this week with a 6-3, 6-1 pasting of Greek qualifier Eleni Daniilidou.
In other opening-round play involving seeds, Italian Flavia Pennetta dismissed No. 12 Anastasia Pavlyuchenkova of Russia 2-6, 6-3, 6-3, No. 13 Jelena Jankovic whipped Czech Iveta Benesova 6-0, 6-3, No. 16 Peng Shuai of China got past Argentine Gisela Dulko 6-3, 4-6, 6-4, and No. 17 Yanina Wickmayer of Belgium decked Serbian qualifier Bojana Jovanovski 6-3, 6-4. The former world No. 1 and former U.S. Open runner-up Jankovic was the Cincy champion two years ago.
The 2011 Cincinnati champion will collect $360,000.