SUMMARY SETTING Few studies have shown the operational feasibility, safety, tolerability, or outcomes of multi-drug-resistant latent tuberculous infection (MDR LTBI) treatment. After two simultaneous multidrug-resistant tuberculosis (MDR-TB) outbreaks in Chuuk, Federated States of Micronesia, infected contacts were offered a 12-month fluoroquinolone (FQ) based MDR LTBI treatment regimen. DESIGN Between January 2009 and February 2012, 119 contacts of MDR-TB patients were followed using a prospective observational study design. After MDR-TB disease was excluded, 12 months of daily FQ-based preventive treatment of MDR LTBI was provided by directly observed therapy. RESULTS Among the 119 infected contacts, 15 refused, while 104 began treatment for MDR LTBI. Of the 104 who initiated treatment, 93 (89%) completed treatment, while 4 contacts discontinued due to adverse effects. None of the 104 contacts who undertook MDR LTBI treatment of any duration developed MDR-TB disease; however, 3 of 15 contacts who refused and 15 unidentified contacts developed MDR-TB disease. CONCLUSION Providing treatment for MDR LTBI can be accomplished in a resource-limited setting, and contributed to preventing MDR-TB disease. The Chuuk TB program implemented treatment of MDR LTBI with an 89% completion rate. The MDR LTBI regimens were safe and well tolerated, and no TB cases occurred among persons treated for MDR LTBI.