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Context: Adolescent offspring of depressed parents are at markedly increased risk of developing depressive disorders. Although some smaller targeted prevention trials have found that depression risk can be reduced, these results have yet to be replicated and extended to large-scale, at-risk populations in different settings.Objective: To determine the effects of a group cognitive behavioral (CB) prevention program compared with usual care in preventing the onset of depression.Design, Setting, and Participants: A multicenter randomized controlled trial conducted in 4 US cities in which 316 adolescent (aged 13-17 years) offspring of parents with current or prior depressive disorders were recruited from August 2003 through February 2006. Adolescents had a past history of depression, current elevated but subdiagnostic depressive symptoms, or both. Assessments were conducted at baseline, after the 8-week intervention, and after the 6-month continuation phase.Intervention: Adolescents were randomly assigned to the CB prevention program consisting of 8 weekly, 90-minute group sessions followed by 6 monthly continuation sessions or assigned to receive usual care alone.Main Outcome Measure: Rate and hazard ratio (HR) of a probable or definite depressive episode (ie, depressive symptom rating score of > or = 4) for at least 2 weeks as diagnosed by clinical interviewers.Results: Through the postcontinuation session follow-up, the rate and HR of incident depressive episodes were lower for those in the CB prevention program than for those in usual care (21.4% vs 32.7%; HR, 0.63; 95% confidence interval [CI], 0.40-0.98). Adolescents in the CB prevention program also showed significantly greater improvement in self-reported depressive symptoms than those in usual care (coefficient, -1.1; z = -2.2; P = .03). Current parental depression at baseline moderated intervention effects (HR, 5.98; 95% CI, 2.29-15.58; P = .001). Among adolescents whose parents were not depressed at baseline, the CB prevention program was more effective in preventing onset of depression than usual care (11.7% vs 40.5%; HR, 0.24; 95% CI, 0.11-0.50), whereas for adolescents with a currently depressed parent, the CB prevention program was not more effective than usual care in preventing incident depression (31.2% vs 24.3%; HR, 1.43; 95% CI, 0.76-2.67).Conclusion: The CB prevention program had a significant prevention effect through the 9-month follow-up period based on both clinical diagnoses and self-reported depressive symptoms, but this effect was not evident for adolescents with a currently depressed parent.Trial Registration: clinicaltrials.gov Identifier: NCT00073671. [ABSTRACT FROM AUTHOR]