AIM: To compare the in vitro activity of the anti-impetigo agent, ozenoxacin, and other antimicrobial agents against Gram-positive clinical isolates from skin and soft tissue infections. MATERIALS & METHODS: Isolates were collected in two studies: 1097 isolates from 49 centers during 2009-2010 and 1031 isolates from ten centers during 2014. Minimum inhibitory concentrations were determined for 18 and 11 antimicrobials in these studies, respectively, using standard broth microdilution methods. Isolates were stratified by species and methicillin susceptibility/resistance and/or levofloxacin susceptibility/nonsusceptibility status. RESULTS: Ozenoxacin exhibited high in vitro activity against Staphylococcus aureus and coagulase-negative staphylococci isolates in both studies. Ozenoxacin was also highly active against Streptococcus pyogenes and Streptococcus agalactiae isolates. CONCLUSION: Ozenoxacin is a potent antimicrobial agent against staphylococci and streptococci.