In vitro activities of ciprofloxacin, fleroxacin, lomefloxacin, ofloxacin, and seven other oral antimicrobials including amoxicillin-clavulanic acid (A/C), oxacillin, cefaclor, cefixime, cefuroxime, erythromycin, and trimethoprim-sulfamethoxazole (T/S) were evaluated against 1708 fresh bacterial isolates from four hospital laboratories approximately 4 years after the introduction of ciprofloxacin. T/S and ofloxacin had the lowest MIC90s and greatest percentage of susceptible strains overall, followed by the other three quinolones. Quinolones were the most active drugs tested against Gram-negative bacteria, with little variation in the activity among the four compounds against most species. Quinolone resistance was detected to some degree in the majority of Gram-negative species tested, with Pseudomonas, Acinetobacter, Xanthomonas, and Providencia demonstrating the highest percentage of resistant strains. Ofloxacin and ciprofloxacin were relatively more active against Gram-positive bacteria than were fleroxacin and lomefloxacin, but T/S and A/C had more susceptible strains than any of the quinolones. Oxacillin-resistant staphylococci, enterococci, and streptococci exhibited the least quinolone susceptibility. This study showed that while resistance is developing among several previously susceptible bacterial species, quinolones remain important alternatives for the oral treatment of many types of infections. Actions to prevent or limit resistance will be important to maintain the viability of the quinolones as therapeutic agents in both hospital and community environments.