Background: Adolescent depression and suicidality is a global mental health concern. Early identification and effective prevention can contribute to reducing the risk of developing these mental health problems. For adolescents, school-based prevention has shown to be feasible. Yet, there is limited evidence for the real life effectiveness, as implementation seems to suffer from the large gap between research and practice. Methods: We examined the effectiveness of prevention for high-risk adolescents when fully implemented in school communities. Two RCTs were performed, with over 5000 adolescents for each trial being screened for elevated depressive symptoms and suicidality. In the first RCT, 130 adolescents aged between 12 and 16 years old were randomly assigned to the intervention (CBT-based prevention) or control condition (psycho-education). Adolescents and their parents were monitored up to 24 months post-intervention. In the second RCT, schools were randomly assigned to the intervention (STORM) or control condition (gatekeepers and early detection). Adolescents were monitored up to 12 months post-intervention. Results: In the first trial, depressive symptoms decreased over time, and this decrease was larger for the intervention condition. This indicates that CBT based prevention might ensure sustainable outcomes when implemented in school communities. In the second trial, no clinical significant differences were observed between conditions. However, the measurements of the latter RCT were performed during COVID-19 lockdown, findings need be interpreted with caution. Important to mention, not all adolescents and parents feel the need to participate in prevention; nearly one third of referred adolescents participated. Additional findings showed that health professionals, performing the screening and referral, often do not feel equipped. Conclusion: With continued and still ongoing research focused on closing the gap between early identification and participation rate in the preventive intervention, we aim to increase benefit from prevention. Summarizing, our findings demonstrate the potential of implementing school-based depression prevention, but also show that further research is needed.