Ofloxacin, a newer broad-spectrum fluoroquinolone, was evaluated against 6967 clinical isolates in a multicenter surveillance trial using a standardized disk diffusion method. Thirty-five geographically diverse laboratories contributed zone diameter results for two (ofloxacin and ciprofloxacin) to five (ofloxacin, ciprofloxacin, ampicillin, cefaclor, and cefixime) antimicrobial agents, depending on the site of infection. Ofloxacin was determined to have the widest spectrum of activity and potential empiric use (90.6%, range 87.1%-92.2%) for respiratory tract, urinary tract, and cutaneous infections. The spectrum was superior to ciprofloxacin (average 85.3% versus three sites), ampicillin (35.5%, respiratory tract), cefaclor (60.5%, respiratory tract), cefixime (60.9%, respiratory tract), and norfloxacin (87.3%, urinary tract). Strains resistant to ofloxacin (35 isolates, 0.5%) were confirmed by reference laboratory tests and cross resistance was observed among several current and investigational fluoroquinolone agents. The species most often found to be fluoroquinolone resistant among the Enterobacteriaceae were Klebsiella pneumoniae, Serratia marcescens, and Providencia spp. Monitoring for increasing fluoroquinolone resistance should be considered as greater use of drugs in this class develops. By these cited statistics, ofloxacin appears to have a broad and balanced spectrum of potential use, particularly against Gram-positive pathogens.