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 youths versus controls, i.e. youth in the standard educational setting. Relative to control youths, intervention youths were less likely to use tobacco, with modestly stronger evidence of protection associated with the CC intervention (RR=0.5; P=0.008) as compared to protection associated with the FSP intervention (RR=0.6; P=0.042). Intervention status was not associated with risk of starting alcohol, inhalants, or marijuana use, but assignment to the CC intervention was associated with reduced risk of starting to use other illegal drugs by early adolescence, i.e. heroin, crack, and cocaine powder (RR=0.32, P=0.042). This study adds new evidence on intervention-associated reduced risk of starting illegal drug use. In the context of 'gateway' models, the null evidence on marijuana is intriguing and merits attention in future investigations.