Using data from the Gonococcal Isolate Surveillance Project, we studied changes in ciprofl oxacin resistance in Neisseria gonorrhoeae isolates in the United States during 2002-2007. Compared with prevalence in heterosexual men, prevalence of ciprofl oxacin-resistant N. gonorrhoeae infections showed a more pronounced increase in men who have sex with men (MSM), particularly through an increase in prevalence of strains also resistant to tetracycline and penicillin. Moreover, that multidrug resistance profi le among MSM was negatively associated with recent travel. Across the surveillance project sites, fi rst appearance of ciprofl oxacin resistance in heterosexual men was positively correlated with such resistance for MSM. The increase in prevalence of ciprofl oxacin resistance may have been facilitated by use of fl uoroquinolones for treating gonorrhea and other conditions. The prominence of multidrug resistance suggests that using other classes of antimicrobial drugs for purposes other than treating gonorrhea helped increase the prevalence of ciprofl oxacin-resistant strains that are also resistant to those drugs.