Adolescent depression is a common and recurrent disorder associated with significant impairment and other forms of psychopathology. Finding an effective intervention that prevents depression in adolescents is an important public health priority. Participants were 518 high school students (mean age = 15.09; SD = 0.76) from the mid-south of the United States. Participants were randomly assigned to 1 of 3 conditions: a cognitive-behavioral program (CB; n = 166), nonspecific control (NSp; n = 175), or a no-intervention control condition (NIC; n = 177). Both the CB and NSp conditions consisted of 90-min sessions administered once a week over a 10-week period during regular school hours. Depressive symptoms were assessed with the Children’s Depression Inventory (CDI) at baseline; postintervention; and at 4-, 8-, and 12-month follow-ups. The Time × Condition interaction was significant, F(8, 478.57) = 3.32, p = .001, indicating that at the 4-month follow-up, youth in the CB condition had significantly lower CDI scores compared with those in the NSp (p = .047, g = 0.29; CI [0.06, 0.52]) and the NIC conditions (p = .003, g = 0.30; CI [0.07, 0.53]). Future studies need to examine the importance of theory-driven change mechanisms, interpersonal relationships, and structural circumstances in schools as factors impacting the long-term effects of CB prevention programs.