Regarding Neisseria gonorrhoeae, the National Committee for Clinical Laboratory Standards (NCCLS) has not defined the breakpoint minimum inhibitory concentration (MIC) for expanded spectrum cephems such as cefpodoxime and ceftizoxime, because of the absence of resistant strains to these antibiotics. To date, in gonococcal urethritis, after treatment with third generation cephems and aztreonam, clinical failures caused by resistant N. gonorrhoeae strains have not been reported. However, we experienced two clinical failures in patients with gonococcal urethritis treated with cefdinir and aztreonam. N. gonorrhoeae isolates from these two patients showed high-level MICs to these agents. The MIC of cefdinir was 1 microg/ml for both strains and that of aztreonam was 8 microg/ml for both strains, while the MICs of other beta-lactams were also higher than the NCCLS value, except for ceftriaxone, for which the MIC was 0.125 microg/ml for both strains. Moreover, the MICs of fluoroquinolones, tetracyclines, and erythromycin against these two isolates were higher than the NCCLS susceptibility value. These isolates were susceptible to spectinomycin. In N. gonorrhoeae, the emergence of these beta-lactam-resistant isolates is of serious concern. However, a more serious problem is that these isolates were already resistant to non-beta-lactam antimicrobials. In Japan, ceftriaxone has not been permitted for clinical use against gonococcal infections. Therefore, in Japan, patients with gonococcal urethritis caused by these resistant N. gonorrhoeae strains should be treated with cefodizime or spectinomycin.