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Background: Standard multidrug therapy for leprosy may be associated with severe side effects, which add to the stigma and discrimination that affect persons with the disease. In addition, the threat posed by drug-resistant leprosy shows the need for alternative drug combinations and shorter, safer regimens of multidrug therapy., Methods: In this open-label, proof-of-concept study conducted in Brazil, we assigned patients with previously untreated multibacillary leprosy to receive bedaquiline monotherapy for 8 weeks. After completing the 8-week course of bedaquiline, the patients started standard multidrug therapy (as defined by the World Health Organization) for leprosy and were followed for 112 weeks. The primary end point was the change from baseline in the odds of positive growth of Mycobacterium leprae in mouse footpads after 8 weeks of bedaquiline therapy. The secondary end point was safety. Exploratory end points included change in the clinical signs and symptoms of leprosy and in the molecular viability of M. leprae (measured by a quantitative reverse-transcriptase-polymerase-chain-reaction assay)., Results: A total of nine patients were included in the modified intention-to-treat analysis. The odds of positive M. leprae growth had decreased from 100% in all the patients at baseline to no growth after 4 weeks of bedaquiline monotherapy. After 7 weeks of treatment, all the patients showed improvement in the appearance of skin lesions as compared with baseline. Seven patients had at least one adverse event (all grade 1 or 2) during treatment., Conclusions: In patients with multibacillary leprosy, bedaquiline monotherapy cleared M. leprae by 4 weeks of treatment and led to improvement in the appearance of skin lesions by 7 weeks. (Funded by Janssen Research and Development; ClinicalTrials.gov number, NCT03384641.)., (Copyright © 2024 Massachusetts Medical Society.)