Third seed Stan Wawrinka became the latest high-profile casualty at the Italian Open on Thursday when the Swiss was knocked out in the third round by American John Isner.
Isner took his ace count to 72 in three rounds as he powered past Wawrinka 7-6(1) 6-4 to reach the quarter-finals.
It was his first claycourt win against a top-10 player at an ATP Tour event and his reward is a clash with Croatia's Marin Cilic who beat David Goffin 6-3 6-4.
World number two Novak Djokovic continued to look more like his old self after a slump as he saw off Spanish claycourter Roberto Bautista-Agut 6-4 6-4 on Court Centrale to reach the quarters for an 11th successive year.
Favourite Rafa Nadal's imperious start to the claycourt season continued as he maintained his unbeaten streak on the surface this year with a 6-3 6-4 victory over 13th seeded American Jack Sock.
He will now face Dominic Thiem in the quarter-finals, with the Austrian having become a familiar foe after two previous meetings in the last three weeks.
Earlier there was disappointment for home fans as Fabio Fognini, who beat top seed Andy Murray on Tuesday, was outplayed 6-3 6-3 by Germany's Alexander Zverev.
Fognini failed to reproduce the sparkling form that did for Murray and blew his top in the second set over a line call, arguing with umpire Mohamed Lahyani.
Lahyani got out of his chair to check a mark at Fognini's request, but told the Italian to "stop talking" after the Italian continued to vent his anger.
Zverev, who turned 20 last month, wrapped up the second set 6-3, and will play Canada's Milos Raonic, the number five seed, next after he beat Tomas Berdych.
8-Dominic Thiem (Austria) beat Sam Querrey (U.S.) 3-6 6-3 7-6(7)
4-Rafa Nadal (Spain) beat 13-Jack Sock (U.S.) 6-3 6-4
Juan Martin Del Potro (Argentina) beat 7-Kei Nishikori (Japan) 7-6(4) 6-3
2-Novak Djokovic (Serbia) beat Roberto Bautista (Spain) 6-4 6-4
John Isner (U.S.) beat 3-Stan Wawrinka (Switzerland) 7-6(1) 6-4
5-Milos Raonic (Canada) beat 12-Tomas Berdych (Czech Republic) 6-3 6-2
6-Marin Cilic (Croatia) beat 9-David Goffin (Belgium) 6-3 6-4
16-Alexander Zverev (Germany) beat Fabio Fognini (Italy) 6-3 6-3