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RATIONALE Completion of preventive therapy is a major bottleneck in global tuberculosis control. Long-acting injectable drug formulations would shorten therapy administration and may thereby improve completion rates. Recently, a long-acting formulation of bedaquiline demonstrated anti-tuberculosis activity for up to 12 weeks post-injection in a validated mouse model of preventive therapy. OBJECTIVES The objectives of this study were to (i) determine the total duration of activity following an injection of long-acting bedaquiline, and (ii) evaluate the activity of regimens comprised of long-acting bedaquiline plus short (2-4 week) oral companion courses of bedaquiline, with or without rifapentine, using the validated mouse model of tuberculosis preventive therapy. METHODS After establishment of a stable Mycobacterium tuberculosis lung infection in BCG-immunized BALB/c mice, treatment was initiated with one of 12 randomly assigned regimens. In addition to positive and negative controls, six regimens included 1 or 2 injections of long-acting bedaquiline (alone or with oral bedaquiline +/- rifapentine), and 4 comparator regimens consisted of oral agents only. Lung bacterial burden was measured monthly for up to 28 weeks. MEASUREMENTS AND MAIN RESULTS One injection of long-acting bedaquiline at 160 mg/kg exerted anti-tuberculosis activity for 12 weeks. Compared to the positive control (daily isoniazid-rifapentine for 4 weeks), six regimens had equivalent bactericidal activity (including two all-oral comparator regimens), and two regimens has superior sterilizing activity: one injection with 2 weeks of oral bedaquiline and high-dose rifapentine; and 2 injections with 4 weeks of oral bedaquiline. CONCLUSION Long-acting injectable bedaquiline has significant potential for shortening tuberculosis preventive therapy.