Jo-Wilfried Tsonga was one of four players to upset a seed at the Open Sud de France on Wednesday, while Juan Ignacio Londero won again on home soil in Argentina.
Only Jeremy Chardy progressed of the five seeded players in action in Montpellier on Wednesday, with Tsonga's 6-2, 7-6 (7-3) defeat of fellow Frenchman Gilles Simon the most notable result.
The former world number five will now face another compatriot in the quarter-finals as he continues to rebuild his career, with Chardy up next after a straight-sets win over qualifier Antoine Hoang.
David Goffin was involved in the late match of the day, but the second seed was brushed aside by Filip Krajinovic 6-4, 6-4.
Benoit Paire was also beaten by Tomas Berdych, while Philipp Kohlschreiber went down in straight sets to Radu Albot in the first round.
At the Cordoba Open, Londero - who was born in the city - followed up his first ATP Tour win with another victory in a remarkable contest.
Londero defeated fifth seed Nicolas Jarry on Tuesday and then, 24 hours later, saved 10 of the 10 break points he faced to see off Lorenzo Sonego 7-5, 6-3.
He will next face another local in Pedro Cachin, who was trailing Pablo Carreno Busta 7-6 (7-3), 0-1 when the Spanish fourth seed retired due to a right shoulder injury.
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Meanwhile, there were more shocks at the Sofia Open as top seed Karen Khachanov bowed out at the hands of Matteo Berrettini, who rallied from a set down to record an impressive 6-7 (6-8) 6-3 6-4 triumph.
Berrettini's fellow Italian Andreas Seppi - seeded eighth for the tournament - was beaten by home hopeful Marton Fucsovics in straight sets.
Spanish duo Roberto Bautista Agut and Fernando Verdasco both progressed unscathed, though.