The current study evaluates a depression prevention program for adolescents led by psychologists vs. teachers in comparison to a control. The universal school-based prevention program has shown its efficacy in several studies when implemented by psychologists. The current study compares the effects of the program as implemented by teachers versus that implemented by psychologists under real-life conditions. A total of 646 vocational track 8th grade students from Germany participated either in a universal prevention program, led by teachers (n = 207) or psychologists (n = 213), or a teaching-as-usual control condition (n = 226). The design includes baseline, post-intervention, and follow-up (at 6 and 12 months post-intervention). The cognitive-behavioral program includes 10 sessions held in a regular school setting in same-gender groups and is based on the social information-processing model of social competence. Positive intervention effects were found on the change in girls’ depressive symptoms up to 12 months after program delivery when the program was implemented by psychologists. No such effects were found on boys or when program was delivered by teachers. The prevention program can successfully be implemented for girls by psychologists. Further research is needed for explanations of these effects.