Background: Since the late 1990s, a global resurgence of gonorrhea and an increase in antibiotic resistance have been observed. Multidrug resistance could lead to a therapeutic impasse. This article describes the evolution of gonococcal antibiotic resistance in France over a 12-year period (2001–2012) as well as the factors associated with the decline in susceptibility to cephalosporins. Method: Surveillance of gonococcal infections is conducted through the Rénago network of volunteer laboratories that collect epidemiological data. Strains are sent to the National Reference Center, which determines the minimum inhibitory concentration (MIC) for six antibiotics. Results: Between 2001 and 2012, the number of gonococcal infections increased steadily. The susceptibility of 8,649 strains was studied during this period. The proportion of resistant strains fluctuated around 13% for penicillin, rose to 56% in 2012 for tetracycline, and increased and remained high at around 42% for ciprofloxacin. The proportion of resistant strains for cefixime (MIC >0.125 mg/L) quadrupled between 2011 (0.7%) and 2012 (3.0%; p<0.001). Only 2 of 8,649 strains had a ceftriaxone MIC >0.125 mg/L, both in 2010. Decreased susceptibility to cephalosporins increases with patient age and is more common in pharyngeal strains. Conclusion: The increase in resistance to cefixime may indicate insufficient adherence to the national recommendation to use ceftriaxone as first-line therapy in the probabilistic treatment of urethritis and cervicitis. Enhanced surveillance of pharyngeal isolates is recommended. (R.A.)