World No. 1 Victoria Azarenka suffered a blow to her French Open preparations when she was forced to pull out of the Italian Open with a right shoulder injury on Wednesday, but an aching Roger Federer gingerly advanced to the third round.
Azarenka had shown no sign of discomfort when she walloped Israel's Shahar Peer 6-1, 6-2 in the second round but the WTA announced her withdrawal shortly after the victory to the surprise of everyone in the Foro Italico.
With just 10 days until the start of the French Open, the Belarusian will hope for a quick recovery ahead of her bid for a second straight grand slam title.
In-form Federer, carrying a few aches and pains after winning the Madrid Masters on Sunday, saw off Carlos Berlocq of Argentina 6-3, 6-4.
The Swiss only decided to play after his morning practice session.
Nadal, beaten in the third round in Madrid, looked far more comfortable as he eased to a 6-1, 7-5 win over German Florian Mayer.
Mayer beat Nadal the last time they played, in Shanghai last year, but on his favoured clay, the Spaniard never allowed him to get a foothold in the match.
Tomas Berdych eased past Lukas Kubot 6-4, 6-1 to reach round three, while Juan Martin Del Potro also advanced.
But American John Isner was upset 2-6, 7-6, 7-5 by Italian Andreas Seppi.
Azarenka's withdrawal handed Dominika Cibulkova of Slovakia a free ticket to the last eight, but Serena Williams had to battle back to beat Russia's Nadia Petrova 4-6, 6-2, 6-3 in the American's second match in 18 hours.
World No. 3 Agnieszka Radwanska lost 6-4, 4-6, 6-1 to Czech Petra Cetkovska, while former World No. 1 Wozniacki, suffering from sinus problems, quit when trailing 6-4, 4-0 to Anabel Medina Garrigues of Spain.