AIM: To assess the effectiveness of the Healthy School and Drugs (HSD) program for secondary schools on the development of substance use among Dutch early adolescents and to explore whether boys, adolescents of lower educational backgrounds, or adolescents high on personality risk traits, would benefit more from the HSD program than others. DESIGN: Randomized clustered trial with two intervention conditions (i.e., lessons and integral) among a general population of adolescents in the Netherlands. PARTICIPANTS: A total of 3784 students of 23 Dutch secondary schools. MEASUREMENTS: Structured digital questionnaires were administered pre-intervention and at 8, 20, and 32months follow-ups. The outcome measure was the rate of change in substance use across follow-ups. Differential effectiveness of the HSD program was examined for sex, educational level, and personality traits. FINDINGS: Our results show no HSD intervention effects on the development of substance use. Sex, education level, and personality characteristics of the participants did not moderate the intervention effects. CONCLUSION: The absence of effects of the Healthy School and Drugs program on the development of substance use indicates that the program should be renewed and redeveloped.