PHOTO: AFP
Muguruza — a former world number one now ranked 19th — came through 6-3, 6-4 for her third win over 46th-ranked Saisai this season.
The 25-year-old Muguruza, who won the French Open in 2016 and Wimbledon in 2017, has twice reached the semi-finals in Rome.
"It was a slow start but I'm happy because last week wasn't a good week for me," Muguruza, who exited the Madrid Open in the first round, told the WTA website.
"I love Rome and it is very important for me to get as many matches as I can for the Grand Slam at the French Open."
She next plays either Denmark's Caroline Wozniacki, the 11th seed, or American Danielle Collins, for a place in the third round.
It was not a good day for Chinese players at the Foro Italico with two-time Australian Open champion Victoria Azarenka crushing Zhang Shuai 6-2, 6-1, and next meets two-time defending Rome champion Elina Svitolina.
Chinese 15th seed Wang Qiang also fell to Czech Katerina Siniakova 1-6, 7-5, 6-4.
Former world number one Serena Williams returned from injury to book a rematch with her sister Venus, 21 years after they last met in Rome.
Four-time Rome winner Serena, 37, eased through 6-4, 6-2 against Swedish qualifier Rebecca Petersen after nearly two months out with a knee injury.
But 38-year-old Venus, whose only Rome title came back in 1999, needed more than three hours to battle past Belgian Elise Mertens 7-5, 3-6, 7-6 (7/4).
The sisters last played each other in the quarter-finals in Rome in 1998, with Venus the winner.
"I love the clay season and wanted to do everything to be a part of it," said Serena, who is one title short of Chris Evert's record of five Rome crowns.
"It's not about today or tomorrow. Obviously the slams, et cetera, just getting ready for those events," added the 23-time Grand Slam winner.
Former world number four Dominika Cibulkova, won her match 6-2, 6-3 against Aliaksandra Sasnovich, and next meets US Open and Australian Open winner Naomi Osaka of Japan.
Britain's Johanna Konta swept aside Alison Riske 6-4, 6-1, and next plays Sloane Stephens.
Italian wildcard Sara Errani fell 6-1, 6-0 to Slovak Victoria Kuzmova.
US 18th seed Madison Keys, a semi-finalist in last year's French Open, beat Slovenia's Polona Hercog 6-4, 7-6 (7/3), and next meets fellow American Sofia Kenin.
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