World number one Andy Murray was sent packing from the Internazionali d'Italia but Novak Djokovic survived, while David Ferrer and Tomas Berdych claimed landmark victories on Wednesday (AEST).
Murray won his first clay-court title in Rome last year but there was to be no repeat of that feat after the top seed was outclassed 6-2 6-4 by Fabio Fognini.
Djokovic lost to Rafael Nadal at the semi-final stage of the Madrid Open last week in his first tournament since parting company with his long-term coaching staff, but responded by defeating Aljaz Bedene 7-6 (7-2) 6-2.
Experienced Spaniard Ferrer racked up his 700th win on the AT World Tour with a 4-6 6-3 6-1 success against compatriot Feliciano Lopez.
Berdych also reached a milestone in the Eternal City, seeing off Carlos Berlocq on Court Pietrangeli 6-3 6-4 for his 600th triumph.
It was a night to remember for Murray, who became the first defending champion since Rafael Nadal in 2008 to lose his opener.
Two breaks of serve saw Fognini jump out to a 4-0 lead in the first set and Murray never recovered as his opponent became the first Italian to beat a world number one since Filippo Volandri in 2007.
"He was taking the ball early, hitting the ball close to the lines and dominating most of the points," Murray said. "Normally during matches your opponent might give you a few opportunities with some errors, and obviously you hope to create a few yourself. That certainly wasn't the case. The only chance I really got was when he was making errors."
Djokovic had a much better time on Tuesday. The four-time champion was broken in the first game of the match, but that was the only time the world number two failed to hold in the match.
"I just wish that I had started a little bit sharper. But hopefully the next one will be good." said the Serbian.
Ferrer was made to wait for a place in the 700 club by Kei Nishikori at the Madrid Open last week, but he was not to be denied in Rome.
The 35 year-old became only the 13th player in ATP World Tour history to reach the landmark and will get a chance to gain revenge over Nishikori in the third round.
Berdych is a century of victories adrift of Ferrer after the 31-year-old Czech ousted qualifier Berlocq in straight sets. Tommy Haas is the oldest player to have won a match at the Internazionali BNL d'Italia following his success against Ernesto Escobedo 6-0 4-6 7-6 (7-1).
David Goffin, Marin Cilic and John Isner were also among the winners in the Italian capital.
Adrian Mannarino was consigned to a straight-sets defeat by Pablo Cuevas in the first round, but the French qualifier conjured up as good a shot as you will see.
Mannarino produced a moment of magic which will take some beating, executing a backhand drop shot which generated so much spin that it returned to his side of the net.