The recent emergence and spread of multidrug resistant P.falciparum strains adds urgency to malaria elimination efforts. After vector control and appropriate case management were established, a village-randomized, controlled trial was conducted in four countries in the Greater Mekong Subregion (GMS): Myanmar, Vietnam, Cambodia, and Lao PDR to assess the effectiveness, safety, tolerability, and acceptability of MDAs. Following intensive community engagement, 16 villages were randomly selected to receive early MDA or serve as controls for 12 months after which the 8 control villages received deferred MDA (MDA 12). The MDA comprised 3-monthly rounds of three doses dihydroartemisinin / piperaquine and a single low-dose primaquine. Exhaustive, cross-sectional surveys of the entire village populations were conducted using uPCR to detect Plasmodium infections. MDAs made a significant impact on P.falciparum prevalence and incidence that persisted over a one-year period. Mobilising populations to participate in multi-round MDAs remains a major challenge for its successful implementation. Rolling out basic malaria control measures, early diagnosis, appropriate treatment, and vector control combined with MDA in transmission hotspots may be the most promising strategy for rapid malaria elimination in the GMS.