Background: Depression in adolescence is associated with long-term adverse consequences. The aim of the present study is to identify target groups at increased risk of developing depression in early adolescence, such that prevention is associated with the largest health benefit at population-level for the least effort. Methods: The analyses were conducted on data of the first (age range 10-12) and fourth (age range 17-20) wave of a population-based cohort study (N=1,538). The Composite International Diagnostic Interview (CIDI) was used to assess onset of major depression in early adolescence. High-risk groups were identified using exposure rate, incidence rate, and population attributable fraction. Results: Prevention of depression onset in early adolescence is best targeted at children with one of the following risk profiles: a high body mass index in combination with (1) maternal depression (2) female gender, and (3) parental emotional rejection. Limitations: Age of onset of depression was assessed retrospectively. Conclusions: Only a few risk indicators are needed to identify a relatively small group which accounts for a substantial percentage of the new cases of depression in early adolescence.