Thirty-six patients with newly diagnosed lepromatous leprosy were allocated randomly to three groups and treated for 56 days with minocycline (100 mg daily), clarithromycin (500 mg daily), or clarithromycin (500 mg) plus minocycline (100 mg daily). All groups had rapid and remarkable clinical improvement and significant decline of the bacterial and morphologic indices in skin smears during treatment. More than 99% and > 99.9% of the viable Mycobacterium leprae had been killed by 28 and 56 days of treatment, respectively, as measured by inoculation of organisms recovered from skin samples, taken before and during treatment, into the footpads of immunocompetent and nude mice. Clinical improvement and bactericidal activity did not differ significantly among the three groups. Adverse reactions were rare and mild, and no laboratory abnormality was detected during the trial. Both clarithromycin and minocycline displayed powerful bactericidal activities against M. leprae in leprosy patients and may be considered important components of new multidrug regimens for the treatment of multibacillary leprosy.