Minimal effective doses of rifabutin and rifampicin were determined in Mycobacterium leprae isolated from skin biopsies of newly diagnosed, previously untreated lepromatous leprosy patients. Rifabutin was more potent than rifampicin. Our previous report that rifabutin was fully active against rifampicin-resistant M. leprae could not be confirmed. Examination of two strains of rifampicin-resistant M. leprae from elsewhere, and a repeat experiment on our original strain of rifampicin-resistant bacilli, showed full cross-resistance between rifampicin and rifabutin. A clinical trial in three newly diagnosed, previously untreated lepromatous patients showed that rifabutin has rapid bactericidal activity.