In the women's tournament, Spaniard Garbine Muguruza dispatched American Sloane Stephens in straight sets with Russian Svetlana Kuznestova battling through for her first win since the tennis restart.
Muguruza, the 2016 French Open champion and seeded ninth in Rome, eased through 6-3, 6-3 behind closed doors on the red clay at the Foro Italico.
It was a tricky opener for Muguruza against former US Open winner Stephens who also has a pedigree on clay, reaching the final in Roland Garros two years ago.
Muguruza hit 22 winners and broke Stephens four times, despite an hour-long rain delay.
She next meets 16-year-old American Coco Gauff, who got her first career main draw win on clay against Ons Jabeur of Tunisia 6-4, 6-3.
"I knew I had a tough match against Sloane," said Muguruza.
"I'm just happy with my performance since is just the third match I am able to play in a long time."
Gauff, ranked 53, struggled with her serve with seven double faults but battled back from a 4-2 deficit in the first set against her Tunisian rival who hit 29 unforced errors.
Former French Open winner Kuznetsova had a tougher battle with American Bernarda Pera before pulling through 3-6, 7-6 (7/3), 6-3.
The two-time Grand Slam champion came from a set and a break down and a 3-0 deficit in the tiebreak to set up a meeting with Estonian 14th seed Anett Kontaveit.
The switch from hard court at the US Open to clay proved tricky for former world number one Angelique Kerber, who reached the fourth round at Flushing Meadows.
Kerber, the 15th seed, fell 6-3, 6-1 to Czech Katerina Siniakova who next plays Daria Kasatkina of Russia.
Collated results from the second day of the ATP and WTA clay-court tournament in Rome on Tuesday (x denotes seed):
Salvatore Caruso (ITA) bt Tennys Sandgren (USA) 3-6, 6-3, 7-6 (7/4)
Marco Cecchinato (ITA) bt Kyle Edmund (GBR) 3-6, 7-6 (9/7), 6-2
Lorenzo Musetti (ITA) bt Stan Wawrinka (SUI x10) 6-0, 7-6 (7/2)
Dominik Koepfer (GER) bt Alex De Minaur (AUS) 3-6, 6-3, 7-6 (7/5)
Federico Coria (ARG) bt Jan-Lennard Struff (GER) 6-1, 7-6 (7/5)
Pedro Martinez (ESP) bt Sam Querrey (USA) 6-3, 7-6 (7/3)
Denis Shapovalov (CAN x12) bt Guido Pella (ARG) 6-2, 6-3
Yoshihito Nishioka (JPN) bt Miomir Kecmanovic (SRB) 6-4, 6-1
John Millman (AUS) bt Joao Sousa (POR) 7-5, 7-6 (7/2)
Andrey Rublev (RUS x9) bt Facundo Bagnis (ARG) 6-4, 6-4
Milos Raonic (CAN x13) bt Adrian Mannarino (FRA) 7-6 (7/3), 6-2
Dusan Lajovic (SRB) bt Alejandro Davidovich (ESP) 6-4, 6-4
Yulia Putintseva (KAZ) bt Rebecca Peterson (SWE) 6-2, 6-4
Darya Kasatkina (RUS) bt Vera Zvonareva (RUS) 6-2, 6-2
Katerina Siniakova (CZE) bt Angelique Kerber (GER x15) 6-3, 6-1
Garbine Muguruza (ESP x9) bt Sloane Stephens (USA) 6-3, 6-3
Cori Gauff (USA) bt Ons Jabeur (TUN) 6-4, 6-3
Irina Begu (ROM) bt Elisabetta Cocciaretto (ITA) 6-2, 6-2
Polona Hercog (SLO) bt Kaja Juvan (SLO) 4-6, 6-4, 6-1
Arantxa Rus (NED) bt Iga Swiatek (POL) 7-6 (7/5), 6-3
Marketa Vondrouaov (CZE x12) bt Misaki Doi (JPN) 6-1, 4-6, 6-4
Anett Kontaveit (EST x14) bt Caroline Garcia (FRA) 6-3, 7-6 (7/1)
Svetlana Kuznetsova (RUS) bt Bernarda Pera (USA) 3-6, 7-6 (7/3), 6-3