Aim To evaluate the effectiveness of the Healthy School and Drugs programme on alcohol, tobacco and marijuana use among Dutch early adolescents. Design Randomized clustered trial with two intervention conditions (i.e. e‐learning and integral). Setting General population of 11–15‐year‐old 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 32 months follow‐up. The primary outcome measures were new incidences of alcohol (life‐time and 1‐month prevalence), tobacco (life‐time and 1‐month prevalence) and marijuana use (life‐time prevalence). Findings Main effect analyses showed no programme effects on incidences of alcohol consumption (life‐time prevalence: e‐learning condition: B = 0.102, P = 0.549; integral condition: B = −0.157, P = 0.351; 1‐month prevalence: e‐learning condition: B = 0.191, P = 0.288; integral condition: B = −0.140, P = 0.445), tobacco consumption (life‐time prevalence: e‐learning condition: B = 0.164, P = 0.444; integral condition: B = 0.160, P = 0.119; 1‐month prevalence: e‐learning condition: B = 0.088, P = 0.746; integral condition: B = 0.261, P = 0.093), or marijuana consumption (life‐time prevalence: e‐learning condition: B = 0.070, P = 0.732; integral condition: B = 0.186, P = 0.214). Conclusion The non‐significant impact of the Healthy School and Drugs programme (a Dutch school‐based prevention programme for early adolescents) on incidences of alcohol, tobacco and marijuana use indicates that the programme is either ineffective or implemented inadequately.