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Obesity prevalence is high in Native American (NA) adults, and there is a critical need to establish and implement evidence-based social, behavioral, and policy interventions that are theoretically informed. The use of multilevel, multicomponent (MLMC) interventions has been shown to be an effective strategy for comprehensive health behavior change; however, there is little guidance available in the literature to facilitate implementation in this underserved and understudied population. To decrease obesity and related comorbidities in NA adults, an MLMC intervention called OPREVENT (Obesity Prevention and Evaluation of InterVention Effectiveness in NaTive North Americans) was implemented in 5 rural NA communities to modify the food-purchasing environment, improve diet, and increase physical activity (PA). Five NA communities across the Upper Midwest and Southwest United States were randomly assigned to Immediate ( n  = 3) or Delayed ( n  = 2) Intervention. OPREVENT was implemented in Immediate Intervention community food stores, worksites, schools, and media over 1 y. A community-randomized controlled trial was used to evaluate intervention impact in adults at the individual and institutional levels, with individual-level data being collected on diet, PA, and psychosocial variables at baseline and follow-up; and institutional-level data being collected on food stores, worksites, and schools, media, and process measures. The OPREVENT intervention was one of the first MLMC obesity interventions in this population and provides evidence-based practices for future program development. The purpose of this article is to describe the design, implementation, and evaluation of OPREVENT. This trial was registered at isrctn.com as ISRCTN76144389.