Bernard Tomic and Ivo Karlovic, the top two seeds at the Nastase Tiriac Trophy, crashed out in the second round on Thursday.
First seed Tomic received a bye in the opening round and got his clay season off to a poor start in Bucharest, going down to Robin Haase in a tight contest.
Haase secured a crucial break at 4-4 in a first-set tie-break in order to take the lead, but the world number 21 forced a decider after staving off seven break points in the second set.
Tomic continued to struggle on his serve, however, and the German completed a 7-6 (7-4) 5-7 6-3 triumph in which just eight points separated the two players.
Haase will face Fernando Verdasco in the quarter-finals after the Spaniard overcame qualifier Radu Albot 6-3 6-1.
Big-hitting Karlovic was also on the end of an upset, losing his seventh successive match by going down 6-3 6-4 to Lucas Pouille in just under 61 minutes.
The Croatian second seed produced 10 aces but was less efficient on his first serve than the 22-year-old Frenchman, who set up a quarter-final clash with Paolo Lorenzi following the Italian's 6-2 6-0 win against Taro Daniel.
After beating Illya Marchenko 7-5 6-2, Federico Delbonis is now the highest seed remaining in the competition, while defending champion Guillermo Garcia-Lopez remains in contention following the Spaniard's 6-3 6-3 triumph over Kyle Edmund.
His compatriot Daniel Gimeno-Traver suffered a 6-1 3-6 6-2 loss to Guido Pella, while Marco Cecchinato defeated Damir Dzumhur 6-5 7-6 (7-3).