The purpose of this study was to determine effect of repeated exposure to sub-inhibitory concentrations of amoxicillin/clavulanic acid on the development of resistance in Streptococcus pneumoniae. Other agents, azithromycin, cefaclor and levofloxacin, were also tested. Twenty S. pneumoniae were passaged for 9 days in the presence of sub-inhibitory concentrations of each antimicrobial agent and MICs determined by NCCLS macro-dilution method. There was a four-fold increase in amoxicillin/clavulanic acid MICs for 2 of 20 isolates. Three of 9 tested against cefaclor, 11 of 13 tested against azithromycin and 9 of 20 tested against levofloxacin showed ≥4-fold increase. Amoxicillin/clavulanic acid was the most stable of the agents tested. Cefaclor MICs were also fairly stable. Azithromycin and levofloxacin MICs were most affected.