Background: Adolescent depression is a global mental health concern. Identification and effective prevention in an early stage are necessary. The present randomized, controlled trial aimed to examine the effectiveness of Cognitive Behavioral Therapy (CBT)-based depression prevention in adolescents with elevated depressive symptoms. This prevention approach is implemented in school communities, which allows to examine effects under real-life circumstances. Methods: A total of 5222 adolescents were screened for elevated depressive symptoms in the second grade of secondary schools; 130 adolescents aged between 12 and 16 years old (M = 13.59; SD = 0.68; 63.8% girls) were randomly assigned to the experimental (OVK 2.0) or control condition (psycho-education). Self- and parent-reported depressive symptoms were assessed at pretest and post intervention, as well as 6- and 12-months follow-up. Clinical assessment of depression was assessed at pretest and 6-months follow-up. Results: Intent-to-treat analyses revealed that the decrease in adolescent-rated depressive symptoms was significantly larger in the intervention condition than in the control condition. There was no significant difference in decrease of parent-rated depressive symptoms between both conditions. Conclusions: Based on the findings, we recommend the implementation of screening and prevention in schools, according the basics of this study design. Since this is a new step forward, we discuss the clinical impact and challenges, as well possibilities for future research. Trial registration: The study is registered in the Dutch Trial Register for RCT's (NTR5725). Date registered: 11 March 2016.