The susceptibility of Legionella pneumophila to a new quinolone, fleroxacin, was studied in both an extra- and an intracellular system. The activity of fleroxacin was compared with that of erythromycin, cefoxitin, and rifampicin. In the extracellular system, erythromycin inhibited while cefoxitin killed the organism. Extracellularly, fleroxacin performed similarly to cefoxitin. Rifampicin was initially bactericidal for L. pneumophila but resistant bacteria emerged at 48 h. The Horwitz monocyte model was used for studies of intracellular antimicrobial activity. At ten times the MIC, cefoxitin did not inhibit intracellular L. pneumophila. Fleroxacin was as active as erythromycin and rifampicin in inhibiting intracellular L. pneumophila. No intracellular, rifampicin-resistant L. pneumophila emerged. Addition of rifampicin to cefoxotin, erythromycin or fleroxacin provided neither synergy nor antagonism.