Background: Suicidal behaviours in adolescents are a major public health problem and evidence-based prevention programmes are greatly needed. We aimed to investigate the efficacy of school-based preventive interventions of suicidal behaviours. Methods: The Saving and Empowering Young Lives in Europe (SEYLE) study is a multicentre, cluster-randomised controlled trial. The SEYLE sample consisted of 11 110 adolescent pupils, median age 15 years (IQR 14-15), recruited from 168 schools in ten European Union countries. We randomly assigned the schools to one of three interventions or a control group. The interventions were: (1) Question, Persuade, and Refer (QPR), a gatekeeper training module targeting teachers and other school personnel, (2) the Youth Aware of Mental Health Programme (YAM) targeting pupils, and (3) screening by professionals (ProfScreen) with referral of at-risk pupils. Each school was randomly assigned by random number generator to participate in one intervention (or control) group only and was unaware of the interventions undertaken in the other three trial groups. The primary outcome measure was the number of suicide attempt(s) made by 3 month and 12 month follow-up. Analysis included all pupils with data available at each timepoint, excluding those who had ever attempted suicide or who had shown severe suicidal ideation during the 2 weeks before baseline. This study is registered with the German Clinical Trials Registry, number DRKS00000214. Findings: Between Nov 1, 2009, and Dec 14, 2010, 168 schools (11 110 pupils) were randomly assigned to interventions (40 schools [2692 pupils] to QPR, 45  YAM, 43  ProfScreen, and 40  control). No significant differences between intervention groups and the control group were recorded at the 3 month follow-up. At the 12 month follow-up, YAM was associated with a significant reduction of incident suicide attempts (odds ratios [OR] 0.45, 95% CI 0.24-0.85; p = 0.014) and severe suicidal ideation (0.50, 0.27-0.92; p = 0.025), compared with the control group. 14 pupils (0.70%) reported incident suicide attempts at the 12 month follow-up in the YAM versus 34 (1.51%) in the control group, and 15 pupils (0.75%) reported incident severe suicidal ideation in the YAM group versus 31 (1.37%) in the control group. No participants completed suicide during the study period. Interpretation: YAM was effective in reducing the number of suicide attempts and severe suicidal ideation in school-based adolescents. These findings underline the benefit of this universal suicide preventive intervention in schools.