Playing her first tennis in seven weeks, studded Sony Ericsson Open.
The 10th-seeded Williams waltzed past Chinese wild card Zhang Shuai 6-2, 6-3 in 1 hour, 20 minutes on the hardcourts at the Tennis Center at Crandon Park.
The former world No. 1 Williams is a five-time Miami champ (2002-04, 2007-08) and two-time runner-up. Last year's U.S. Open runner-up will meet Italian Roberta Vinci in the round of 32 here.
Meanwhile, another former top-ranked star, Kim Clijsters, posted her second win in two days with a 6-2, 7-5 ousting of 14th-seeded German Julia Goerges.
The oft-injured 28-year-old Clijsters, playing her first tennis since the Australian Open in January, is a four-time major champion and was a Miami titlist in 2005 and 2010.
In other action involving top-16 seeds, No. 12 German Sabine Lisicki leveled Swede Sofia Arvidsson 6-3, 6-2 and rising German Mona Barthel bounced No. 13 Serb Jelena Jankovic 6-0, 6-3. The former world No. 1 Jankovic, the Sony Ericsson runner-up in 2008, has now lost her last three matches overall, including her opener at Indian Wells two weeks ago.
A 21st-seeded Vinci moved on with a 7-5, 6-1 victory over Bulgarian Tsvetana Pironkova, while 23rd-seeded Belgian Yanina Wickmayer dismissed New Zealand's Marina Erakovic 6-3, 6-4, and South African Chanelle Scheepers doused 25th- seeded Spaniard Anabel Medina Garrigues 1-6, 6-4, 6-0.
The top seed here is also the defending champion, Victoria Azarenka, who is fresh off her title at Indian Wells. The current world No. 1 star and Australian Open titlist is off to a perfect 23-0 start this season.
The Belarusian Azarenka, who also titled in Miami in 2009, topped three-time Sony Ericsson Open runner-up Maria Sharapova in last week's finale at Indian Wells and last year's title tilt at Crandon Park.
The winner of the $4.828 million tournament will collect $712,000.