Forty-five previously untreated lepromatous leprosy patients were allocated randomly to three groups and treated, respectively, with Regimen A, standard dosage of clofazimine (CLO) in multidrug therapy (MDT) regimen; Regimen B, CLO 600 mg once every 4 weeks; and Regimen C, CLO 1200 mg once every 4 weeks. The duration of the trial was 24 weeks. By the end of the trial, although a few patients in each group did not improve at all clinically, the majority of patients showed clinical amelioration but the responses were slow. While the mean morphological index dropped to the baseline after 24 weeks of treatment, the mean bacterial index did not change significantly. About 80% of the patients in each group remained nasal-smear positive at the end of the trial, but the bacterial loads steadily declined. No significant difference has been detected in these parameters among the three groups. The patients tolerated the regimens very well and the side effects were mild. The results of serial mouse foot pad inoculation demonstrated that the positivity rates of multiplication of Mycobacterium leprae in mice and the proportions of viable organisms reduced gradually in all groups. Because the positivity rate at week 24 in Group C did not differ significantly from Group A, but was significantly smaller than that of Group B, we conclude that Regimen C was as active as Regimen A and could be applied for monthly supervised treatment along with rifampin; Regimen B is less effective and should not be used for the treatment of leprosy.