In the course of a clinical trial of acedapsone therapy in 17 patients with lepromatous leprosy, the rate of response to therapy was measured by inoculation of mice with Mycobacterium leprae recovered from biopsy specimens of skin lesions obtained before treatment and at intervals of 4, 12, and 24 weeks after institution of treatment. The susceptibility of each isolate of M. leprae to dapsone (4,4'-diaminodiphenylsulfone [DDS]) was measured by passaging organisms that had multiplied in mice to new groups of untreated mice and to mice treated with DDS incorporated in the mouse chow in concentrations of 10(-5), 3 x 10(-5), and 10(-4) g/100 ml. The rate of response to acedapsone therapy and the susceptibility of patient strains of M. leprae to DDS varied widely among patients. All isolates were inhibited from multiplication by treatment of mice with 10(-4) g of DDS per 100 ml; all but two isolates were susceptible to 3 x 10(-5) g of DDS per 100 ml; and 17 of 36 isolates, representing nine patient strains, were susceptible to 10(-5) g of DDS per 100 ml. Plasma levels of DDS measured in the mice administered these diets show that the minimal inhibitory concentration of DDS for M. leprae isolated from untreated patients is about 3 ng/ml. No relationship could be demonstrated between DDS susceptibility of pretreatment isolates of M. leprae and the rate at which patients responded to acedapsone therapy. Neither acedapsone treatment of patients nor DDS treatment of mice appeared to select genotypically more resistant M. leprae.