IMPORTANCE: Adolescent offspring of depressed parents are at high risk for experiencing depressive disorders themselves. OBJECTIVE: To determine whether the positive effects of a group cognitive-behavioral prevention (CBP) program extended to longer-term (multiyear) follow-up. DESIGN: A 4-site randomized clinical trial with 33 months of follow-up was conducted. Recruitment of participants was from August 2003 through February 2006. SETTING: The study settings included a health maintenance organization, university medical centers, and a community mental health center. PARTICIPANTS: Three hundred sixteen adolescent (aged 13-17 years) offspring of parents with current and/or prior depressive disorders; adolescents had histories of depression, current elevated depressive symptoms, or both but did not currently meet criteria for a depressive disorder. INTERVENTIONS: The CBP program consisted of 8 weekly 90-minute group sessions followed by 6 monthly continuation sessions. Adolescents were randomly assigned to either the CBP program or usual care (UC). MAIN OUTCOMES AND MEASURES: The primary outcome was a probable or definite episode of depression (Depression Symptom Rating score ≥4) for at least 2 weeks through the month 33 follow-up evaluation. RESULTS: Over the 33-month follow-up period, youths in the CBP condition had significantly fewer onsets of depressive episodes compared with those in UC. Parental depression at baseline significantly moderated the intervention effect. When parents were not depressed at intake, CBP was superior to UC (number needed to treat, 6), whereas when parents were actively depressed at baseline, average onset rates between CBP and UC were not significantly different. A 3-way interaction among intervention, baseline parental depression, and site indicated that the impact of parental depression on intervention effectiveness varied across sites. CONCLUSIONS AND RELEVANCE: The CBP program showed significant sustained effects compared with UC in preventing the onset of depressive episodes in at-risk youth over a nearly 3-year period. Important next steps will be to strengthen the CBP intervention to further enhance its preventive effects, improve intervention outcomes when parents are currently depressed, and conduct larger implementation trials to test the broader public health impact of the CBP program for preventing depression in youth. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00073671.