Project Summary/Abstract In most countries approaching elimination, Plasmodium vivax (Pv) represents an increasing proportion relative to P. falciparum (Pf). Mass drug administration (MDA), as a way target subpatent, asymptomatic infections, is recommended for P. falciparum elimination, but the recommendation does not extend to P. vivax given limited evidence, tools, and safety concerns. The objective of our study is to evaluate the long-term impact, safety, and cost-effectiveness of focal MDA (fMDA) for Pv transmission reduction. To test our hypothesis that fMDA, in addition to standard aggressive interventions, will safely reduce transmission, we propose a 3-year open-label CRCT in the low endemic setting of Loreto Region, Peru. Villages or clusters will be randomized to control or fMDA. The control arm will receive standard interventions (vector control, symptomatic case management, and active case detection of asymptomatic cases). The treatment arm will receive standard interventions plus fMDA, which will utilize a new drug for radical cure of P. vivax, tafenoquine, and a new quantitative glucose 6 phosphate dehydrogenase (G6PD) deficiency rapid test to support safe administration of tafenoquine. fMDA will be targeted to consenting and eligible high-risk villagers, defined as household members and neighbors of recent Pv index cases. fMDA will be conducted in 2 rounds per year, two months apart during the low malaria season, and over 3 years. Eligibility will be re-assessed each year, and prior to each fMDA round. Specific aims are to: 1) Determine the effectiveness of fMDA to reduce Pv transmission as measured in a primary outcome of incidence and secondary outcomes of infection prevalence, seroprevalence, and genetic diversity, 2) Evaluate the safety and tolerability of fMDA, and 3) Measure the cost-effectiveness of fMDA. To maximize