Mycobacterium leprae recovered from skin biopsy specimens of 11 patients with lepromatous leprosy who had not responded to ordinarily adequate sulfone therapy were tested for susceptibility to dapsone in the mouse foot pad. The organisms from five patients were found fully susceptible; two of these patients had discontinued sulfone therapy prematurely, and three had taken dapsone only irregularly or not at all. The organisms from the other six patients were resistant to dapsone—that is, they multiplied in the foot pads of mice to which dapsone had been administered in the diet. Five of the patients with dapsone-resistant organisms were treated with clofazimine (B663) in a dose of 100 to 200 mg daily, and the infectivity of their M. leprae for the mouse foot pad was tested at intervals during treatment; loss of infectivity was interpreted as death of the organisms. As comparison, eight patients with dapsone-susceptible bacilli were treated with dapsone in a dosage of 50 mg daily and the death of their M. leprae was measured by the same procedure. Once started, the rate of bacterial killing was the same in both groups of patients. Killing of dapsone-susceptible M. leprae began immediately after dapsone treatment was started. Killing of dapsone-resistant organisms during B663 therapy did not begin until 50 days after treatment was started.