Clijsters, Venus return with Miami wins
Williams had not played a singles match since last year's US Open in New York when she revealed she had been diagnosed with Sjogren's syndrome, an auto-immune disease that causes fatigue and joint soreness.
But the 31-year-old American was back on the court on Wednesday, beating Japan's Kimiko Date-Krumm 6-0 6-3 in an hour and 17 minutes.
"Just to be in this tournament is a huge win for me," Williams said after being granted a wildcard entry into the tournament.
"Just being here is a win, I told myself going into this, this is a win. Just to train and get back at this level."
Belgium's Clijsters, another former number one on the comeback trail, overcame a slow start before beating Australia's Jarmila Gajdosova 4-6 6-1 6-0.
"It's always tough to get that first match rhythm under your belt," Clijsters said.
"One thing I can count on is I have the experience, though. It doesn't take me that long to get used to it again. But it has become tougher."