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Aims Substance use and binge drinking during early adolescence are associated with neurocognitive abnormalities, mental health problems and an increased risk for future addiction. The trial aims to evaluate the protective effects of an evidence-based substance use prevention programme on the onset of alcohol and drug use in adolescence, as well as on cognitive, mental health and addiction outcomes over 5 years. Design Thirty-eight high schools will be recruited, with a final sample of 31 schools assigned to intervention or control conditions (3826 youth). Brief personality-targeted interventions will be delivered to high-risk youth attending intervention schools during the first year of the trial. Control school participants will receive no intervention above what is offered to them in the regular curriculum by their respective schools. Setting Public/private French and English high schools in Montreal (Canada). Participants All grade 7 students (12-13 years old) will be invited to participate. High-risk youth will be identified as those scoring one standard deviation or more above the school mean on one of the four personality subscales of the Substance Use Risk Profile Scale (40-45% youth). Measurements Self-reported substance use and mental health symptoms and cognitive functioning measured annually throughout 5 years. Primary outcomes are the onset of substance use disorders at 4 years post-intervention (year 5). Secondary intermediate outcomes are the onset of alcohol and substance use 2 years post-intervention and neuropsychological functions; namely, the protective effects of substance use prevention on cognitive functions generally, and executive functions and reward sensitivity specifically. Conclusion This longitudinal, cluster-randomized controlled trial will investigate the impact of a brief personality-targeted intervention program on reducing the onset of addiction 4 years-post intervention. Results will tease apart the developmental sequences of uptake and growth in substance use and cognitive development in adolescence using developmentally sensitive neuropsychological measures. [ABSTRACT FROM AUTHOR]