Coco Vandeweghe battled past Sara Errani to set up a second-round clash with Garbine Muguruza, while Serena Williams pulled out of the WTA Western and Southern Open.
Vandweghe needed three sets to seal the first-round win on Monday, while she was joined in the next round by fellow American Christina McHale, who defeated Saisai Zheng.
Ana Ivanovic - the 2014 runner-up in Cincinnati - faced an early exit after losing in straight sets to Donna Vekic.
Daria Gavrilova, Jelena Ostapenko and Lesia Tsurekno were the others to advance to the next round, eliminating Caroline Garcia, Anna Karolina Schmiedlova and Shuai Zhang respectively.
The American made it through to the next round, but it was no easy task against a resilient Errani.
Vandeweghe had to come from behind to seal a 4-6 6-3 6-4 win in two hours, 22 minutes.
Now, the 24-year-old faces Spanish fourth seed Muguruza in the second round.
"She's a good player, but I can beat here. My power beats her more times than not," a confident Vandeweghe said.
After suffering heartbreak in the women's singles and doubles tournament in Rio, Serena was forced to withdraw from the WTA Premier 5 event.
Serena is the double-defending champion in Cincinnati, but a shoulder injury saw her pull out, with Misaki Doi taking her place.
KERBER'S CHANCE FOR SUPREMACY
With Williams out, Australian Open champion Angelique Kerber has the chance to become the new world number one if she wins in Cincinnati.
The Wimbledon finalist, also runner-up at the W&S Open in 2012, will face either Kateryna Bondarenko or Kristina Mladenovic in the second round.
Muguruza and Vandeweghe meet on Centre Court in the pick of Tuesday's action, while Eugenie Bouchard faces Barbora Strycova.