ABSTRACTThis article describes a feasibility pilot of the linguistically adapted keepin’ it REAL (kiR) substance-use prevention curriculum in Uruguay within the context of marijuana legalization. Originally developed for middle school students in the USA, kiR teaches life skills, risk assessment, and decision-making. Two tuition-free privately managed schools in Montevideo were randomly assigned into intervention and comparison conditions. Trained teachers in the intervention condition delivered kiR to two cohorts of 7th grade students. Before implementation, all students (N = 316) completed pretests; posttests (88% completion) were completed six weeks after the final lesson. We assessed the kiR intervention relative to the comparison group using paired t-tests, baseline adjusted general linear models, and Cohen’s d estimates of effect sizes. The intervention group reported the desired changes in four of six last 30-day substance-use outcomes: relatively smaller increases or actual reductions in frequency of alcohol and marijuana use and in amounts of cigarette and marijuana use. Following an eco-developmental perspective, analysis of the findings considered changing substance-use attitudes, behaviors, and policies in Uruguay. Based on this first evaluation of an evidence-based youth intervention, recommendations for substance-use prevention in the context of drug policy change in Uruguay are offered.