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Prior investigations have linked behavioral competencies in primary school to a reduced risk of later drug involvement. In this randomized prevention trial, we sought to quantify the potential early impact of two developmentally inspired universal preventive interventions on the risk of early-onset alcohol, inhalant, tobacco, and illegal drug use through early adolescence. Participants were recruited as they entered first grade within nine schools of an urban public school system. Approximately, 80% of the sample was followed from first to eighth grades. Two theory-based preventive interventions, (1) a family–school partnership (FSP) intervention and (2) a classroom-centered (CC) intervention, were developed to improve early risk behaviors in primary school. Generalized estimating equations (GEE) multivariate response profile regressions were used to estimate the relative profiles of drug involvement for intervention …