BackgroundAdolescent substance use is associated with both earlier childhood behavioural problems and serious lifetime addiction problems later in life.AimsTo examine whether, and through which mechanisms, targeting risk factors in early childhood prevents substance use across adolescence.MethodDisruptive kindergarten boys (n = 172) living in Montreal were randomly allocated to a preventive intervention and a control condition. The intervention was delivered over 2 years (7–9 years of age) with two main components: (a) social and problem-solving skills training for the boys; and (b) training for parents on effective child-rearing skills.ResultsAdolescent substance use, up to 8 years post-intervention, was reduced in those who received the intervention (d = 0.48−0.70). Of most interest, the intervention effects were explained partly by reductions in impulsivity, antisocial behaviour and affiliation with less deviant peers during pre-adolescence (11–13 years).ConclusionsAdolescent substance use may be indirectly prevented by selectively targeting childhood risk factors that disrupt the developmental cascade of adolescent risk factors for substance use.