Federer, who took over the world No. 2 spot following his Sunday victory at the Madrid Open, moved on with an efficient 6-3, 6-4 win over Argentine Carlos Berlocq.
The second-seeded Swiss superstar advanced to face former world No. 1 and French Open champion Juan Carlos Ferrero.
Five-time Rome winner and No. 2 seed Nadal eased past German Florian Mayer 6-1, 7-5 on the red clay courts of the Foro Italico, without allowing his opponent a single break-point chance.
The Spaniard goes on to face countryman Marcel Granollers in a Thursday matchup.
Tomas Berdych humbled Poland's Lukasz Kubot 6-4, 6-1, and 10th-seeded Argentine star Juan Martin del Potro trounced Russian Mikhail Youzhny 6-4, 6-2.