We investigated the enhancement of the antimicrobial activities of beta-lactams against cefixime (CFIX)-resistant Neisseria gonorrhoeae in the presence of macrolides. Ten strains of CFIX-resistant N. gonorrhoeae, isolated between 2000 and 2003 from male patients with urethritis at Jikei University Affiliated Hospital and its related clinics in the Tokyo metropolitan area, were tested. The fractional inhibitory concentrations of clavulanic acid/amoxicillin (CVA/AMPC), CFIX, or cefteram (CFTM), in the presence of clarithromycin (CAM) or azithromycin (AZM), against these strains were determined. Synergism, partial synergism, or additivity was recognized between CVA/AMPC or CFTM and macrolides against nine strains. Additivity and partial synergism between CFTM and macrolides against nine and ten strains, respectively, were also recognized. On the other hand, antagonism between CFIX and macrolides was recognized. These results indicate that combination antimicrobial chemotherapy, using CFTM or CVA/AMPC with macrolides, is a possible alternative treatment for CFIX-resistant N. gonorrhoeae infections.