Patients with previously untreated lepromatous leprosy were treated by injections of acedapsone (DADDS), a repository sulfone given at 77-day intervals. The response to therapy was evaluated primarily by the results of inoculation of mice with Mycobacterium leprae from serially obtained skin punch biopsy specimens. In 3 of 10 patients, infectivity for mice was lost in less than 100 days; in the others the infectivity was lost more slowly, and in the slowest more than 300 days were required. The results were compared with those in 14 patients treated with dapsone (DDS) in dosages of 50 mg daily; in 12 of these, infectivity of the bacilli was not demonstrable after 100 days. Tests of the M. leprae isolates for DDS-sensitivity in mice showed that drug-resistance, in the usual sense, was not involved in the slower loss of infectivity. The implications of this slower response for the long-term therapeutic response to acedapsone are not yet clear.