The appearance of resistance or reduced susceptibility to fluoroquinolones among Hemophilus influenzae has been documented for nearly a decade. Over this time, the use of fluoroquinolones for the treatment of respiratory infections including commonly isolated bacterial causes of community-acquired infections has markedly increased. The documentation of resistance to fluoroquinolones among Streptococcus pneumoniae and H. influenzae has also become more prevalent as measured by peer-reviewed publications. During 1997-2001, a total of 11,355 H. influenzae isolates were tested by reference broth microdilution methods from strains collected by the SENTRY Antimicrobial Surveillance Program (American and European medical centers). Strains with reduced susceptibility to fluoroquinolones (RSF) were detected during all five study years at an overall rate of 0.15%. Among the tested compounds, sitafloxacin (MIC(50,) 0.03 microg/ml) was the most potent agent against the RSF strains, followed by gemifloxacin (0.12 microg/ml) > garenoxacin = grepafloxacin = levofloxacin = moxifloxacin = trovafloxacin (0.5 microg/ml) > ciprofloxacin = sparfloxacin (1 microg/ml). Gene sequencing of the quinolone resistance determining region and epidemiologic typing of 30 RSF isolates showed diverse mutational events in gyr A and par C and multiple pulsed-field gel electrophoresis (PFGE) patterns among strains that was not consistent with clonal dissemination. Continued surveillance by global or national networks should continue to monitor for H. influenzae isolates that are refractory to fluoroquinolone therapy.