Legionella organisms are often associated with respiratory infections, and Legionella pneumonia results in significant mortality unless it is promptly and effectively treated. The present study was undertaken to compare the in vitro activity of BMS-284756 (T-3811ME), a novel des-F(6)-quinolone, against Legionella species versus the activity of other fluoroquinolones (levofloxacin, moxifloxacin, and ciprofloxacin) and of the macrolides erythromycin, clarithromycin, and azithromycin. The most potent agents tested against Legionella pneumophila serogroup 1, the largest group tested, were BMS-284756, moxifloxacin, and levofloxacin (MIC(90) = 0.016 mg/L). The MIC(90) range for BMS-284756 was 0.008-0.03 mg/L against the total panel of L pneumophila serogroups 1-9 and 12, with the lowest MIC(90) observed for serogroup 7 and the highest for serogroup 2. BMS-284756 was one of the most potent agents tested against isolates of L micdadei, L longbeachae, and other Legionella species (MIC(90) range: 0.008-0.06 mg/L). These results and the high intrinsic activity of BMS-284756 against other respiratory pathogens support its use as empiric monotherapy for a wide range of respiratory infections.