The competition often provides an array of shocks and holders Lille and Girondins Bordeaux narrowly avoided joining their Ligue 1 counterparts on the Cup scrapheap.
Four-times winners Auxerre were humbled 2-1 at home by second-tier Chateauroux, who triumphed thanks to a two-minute double from Maxime Bourgeois just after the half-hour mark.
Lille were given a mighty scare against fourth-tier Compiegne before Bruno Gianni's goal after 114 minutes sealed a 1-0 extra-time win.
Last season's league and cup double winners laboured against their north eastern neighbours and Compiegne almost pulled off a shock but Hubert Aulon's second-half drive grazed the bar.
"What counts in the cup is going through. To go far in the cup you sometimes have to get through via the back door," Lille coach Rudi Garcia told reporters.
