School-based interventions are considered a promising effort to prevent the occurrence of mental disorders in adolescents. This systematic review focuses on school-based prevention interventions on depression and anxiety disorders utilizing an RCT design, starting from the year 2000. Based on an online search (PubMed, Scirus, OVID, ISI) and bibliographic findings in the eligible articles, 28 studies providing information were reviewed. The search process ended on 2 May 2011. The majority of interventions turn out to be effective, both for depression (65%) and anxiety (73%). However, the obtained overall mean effect sizes calculated from the most utilized questionnaires can be considered rather small (CDI: -0.12; RCMAS: -0.29). The majority of the reviewed school-based interventions shows effectiveness in reducing or preventing mental disorders in adolescents. However, effect size computation revealed only small-scale effectiveness. Future studies have to consider the impact of program implementation variations.