Defending champion Andy Murray has continued to struggle on clay court this year following his ouster from the Italian Open in the second round by Italian Fabio Fognini.
The 30-year-old British world number one, whose victory in Rome last year was one of nine titles he won in 2016, lost 6-2 6-4 to the world number 29.
The loss continues Murray’s poor form ahead of the French Open, which gets under way on 28 May.
Murray’s fellow Brit Aljaz Bedene was also knocked out in the second round by world number two Novak Djokovic.
The Serb, who has never failed to reach the last eight in Rome, dominated the tie-break to win a tight first set but eased through the second to win 7-6 (7-2) 6-2.
“A little bit of a slow start, but Bedene is the kind of player that gives you good rhythm,” said Djokovic, who was beaten in the Madrid Open semis by Rafael Nadal last week.
“I had some good exchanges, some good games with rallies and it felt right, especially in the second set.”
Murray, who turned 30 on Monday, continues to struggle for consistency on his return from an elbow injury.
He has won one event this season – on the hard court in Dubai in February – but has struggled on clay, with his best performance in the four events he has played so far on the surface being his semi-final appearance in Barcelona.