The fluoroquinolones ciprofloxacin and ofloxacin are among the antimicrobials recommended for treating uncomplicated gonorrhea. Fluoroquinolone-resistant strains of Neisseria gonorrhoeae have been identified frequently during the 1990s in the Far East. In the United States, fluoroquinolone-resistant N. gonorrhoeae has been reported sporadically; resistance associated with clinical treatment failure has been reported previously in only one person, who probably acquired the infection in the Philippines. This report describes the results of an investigation in 1997 of two cases of gonococcal infection in the United States with strains with a higher level of fluoroquinolone resistance than reported previously; clinical treatment failure occurred in one case.