The mutant prevention concentration (MPC) represents a threshold above which the selective proliferation of resistant mutants is expected to occur only rarely. A provisional MPC (MPC_pr) was defined and measured for five fluoroquinolones with clinical isolates of Streptococcus pneumoniae. Based on their potential for restricting the selection of resistant mutants, the five fluoroquinolones, in descending order, were found to be moxifloxacin > trovafloxacin > gatifloxacin > grepafloxacin > levofloxacin. For several compounds, 90% of about 90 clinical isolates that lacked a known resistance mutation had a value of MPC_pr that was close to or below the serum levels that could be attained with a dosing regimen recommended by the manufacturers. Since MPC_pr overestimates MPC, these data identify moxifloxacin and gatifloxacin as good candidates for determining whether MPC_pr can be used as a guide for choosing and eventually administering fluoroquinolones to significantly reduce the development of resistance.