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Approximately 20% of people will experience a depressive episode by adulthood, making adolescence an important developmental target for prevention. CATCH-IT (Competent Adulthood Transition with Cognitive-behavioral, Humanistic, and Interpersonal Training), an online depression prevention intervention, has demonstrated efficacy in preventing depressive episodes among adolescents reporting elevated symptoms. Our study examines the effects of CATCH-IT compared to online health education (HE) on internalizing symptoms in adolescents at risk for depression. Participants, ages 13-18, were recruited across eight US health systems and were randomly assigned to CATCH-IT or HE. Assessments were completed at baseline, 2, 6, 12, 18, and 24 months. There were no significant differences between groups in change in depressive symptoms (b = -0.31 for CATCH-IT, b = -0.27 for HE, p = 0.80) or anxiety (b = -0.13 for CATCH-IT, b = -0.11 for HE, p = 0.79). Improvement in depressive symptoms was statistically significant ( p < 0.05) for both groups ( p = 0.004 for CATCH-IT, p = 0.009 for HE); improvement in anxiety was significant for CATCH-IT ( p = 0.04) but not HE ( p = 0.07). Parental depression and positive relationships with primary care physicians (PRPC) moderated the anxiety findings, and adolescents' externalizing symptoms and PRPC moderated the depression findings. This study demonstrates the long-term positive effects of both online programs on depressive symptoms and suggests that CATCH-IT demonstrates cross-over effects for anxiety as well.