Patients with previously untreated borderline-lepromatous or fully lepromatous leprosy were treated with one of five clofazimine (B663) regimens: 1) 200 mg daily 6 days per week; 2) 100 mg three times weekly; 3) 300 mg weekly; 4) 600 mg every other week; and 5) 600 mg on 2 consecutive days every 4 weeks. After 24 weeks of treatment, the patients were randomly allocated to treatment either with 200 mg B663 daily 6 days per week (regimen 6) or with dapsone, beginning with a small dosage and increasing over a period of 8 weeks to 100 mg daily 6 days per week (regimen 7). Death of Mycobacterium leprae was monitored by mouse inoculation with organisms recovered from skin biopsy specimens obtained at intervals during the first 24 weeks. Killing of M. leprae proceeded most rapidly in regimen 1 and 2 patients, least rapidly in the patients of regimens 4 and 5, and at an intermediate rate in regimen 3 patients. Erythema nodosum leprosum (ENL) was no more frequent nor more severe during treatment with any one of the first-24-weeks regimen. ENL was more frequent in regimen 7 than in regimen 6 patients. Pigmentation of the skin, assessed only during the first 24 weeks, occurred in patients of all regimens, but was most marked in regimen 1 patients. No evidence of B663 toxicity was noted. Although of all of the first 24-weeks regimens were effective in terms of the rate of killing of M. lepare, greater effectiveness was associated with more frequent administration of the drug. The B663 that accumulated in the tissues did not appear to be available to exert an antimicrobial effect.