The efficacy of three fluorinated quinolones, clinafloxacin (PD 127391), sparfloxacin (PD 131501) and PD 131628, either alone or in combination with rifampicin/rifabutin, against Mycobacterium leprae was evaluated in vitro using two biochemical parameters to measure the metabolic activity of the organism. Clinafloxacin was found to be most effective with an MIC of 0.75 mg/L, followed by sparfloxacin (MIC 1.5 mg/L) and PD131628 (MIC 3.0 mg/L). When combined with rifampicin each of the three quinolones were additive to the activity. However, when combined with rifabutin, both clinafloxacin and sparfloxacin demonstrated pronounced synergic activity. Incorporation of clinafloxacin and rifabutin in a multi-drug therapy regimen is suggested.