Richard Gasquet was the biggest name to fall on a bad day for Frenchmen at the Open 13.
Fifth seed Gasquet suffered a first-round loss to Luxembourgian Gilles Muller, going down 2-6 6-4 7-6 (7-5) in Marseille.
Gasquet looked headed for victory when he raced out to a 5-2 lead in the deciding set but Muller fought back to claim his first Tour-level win of the season.
Usually strong performers in front of their home fans – highlighted by three of the four semi-finalists at the Open Sud de France being French earlier in February – the locals struggled.
Also exiting the ATP 250 tournament were Benoit Paire, runner-up to Gasquet in Montpellier, and Gael Monfils.
Paire was a shock 7-6 (8-6) 6-7 (7-9) 6-4 loser to Indian Somdev Devvarman, the world number 354, while Monfils was downed by Spaniard Marcel Granollers 6-4 6-4.
Left-handed Frenchman Michael Llodra gave the home fans something to cheer about, easily beating Belgian David Goffin 6-2 6-4.
Llodra has an excellent record at the indoor hard-court event, crowned champion in 2010 while being runner-up last year and in 2009.
In a rematch of the 2012 final, Llodra meets Argentine Juan Martin del Potro in the next round.
Wildcard Ernests Gulbis booked a meeting with Czech top seed Tomas Berdych in the second round as the Latvian cruised past Finn Jarkko Nieminen 6-3 6-2.
Russian Nikolay Davydenko overcame Ukrainian qualifier Sergiy Stakhovsky 6-2 4-6 6-2 to set up a clash against French third seed Jo-Wilfried Tsonga.
Spaniard Roberto Bautista-Agut also progressed with a 4-6 7-6 (7-5) 6-0 win over Serbian qualifier Filip Krajinovic.
Meanwhile, Stanislas Wawrinka cruised into the Copa Claro second round, while Pablo Andujar was the only seed to exit.
Switzerland's Wawrinka needed just 58 minutes to thrash Italian Paolo Lorenzi 6-3 6-3, breaking serve three times in his win on the clay courts in Buenos Aires.
The third seed has reached the semi-finals in Argentina, where rain delayed the start of play for four hours, in the past two years.
The ATP 250 event has been dominated by Spaniards in the past four years, with David Ferrer, Nicolas Almagro, Juan Carlos Ferrero and Tommy Robredo all recent champions.
Wawrinka will face a less fancied Spaniard in the second round when he takes on Daniel Gimeno-Traver, who beat Serbian qualifier Dusan Lajovic 6-4 7-5.
Spanish seventh seed Andujar exited, losing to his countryman Albert Montanes 5-7 6-2 6-4 in two hours and 11 minutes.
Montanes converted six of 15 break points in his win and will face Argentine wildcard Federico Delbonis in the second round.
Robredo, the 2009 champion, brushed past Portuguese qualifier Gastao Elias 6-3 6-0, setting up a meeting with Argentine wildcard Diego Sebastian Schwartzman.
Local Leonardo Mayer served 12 aces in his 5-7 6-2 6-3 win over Italy's Simone Bolelli, while German Julian Reister proved too good for Argentine Martin Alund 7-5 6-1.
Russian Andrey Kuznetsov was also victorious, recording a 7-6 (7-5) 6-3 victory against Italian Filippo Volandri.