Investigate factors that amplify or mitigate the effects of an indicated cognitive behavioral (CB) depression prevention program for adolescents with elevated depressive symptoms. Using data from a randomized trial (Registration No. NCT00183417; n = 173) in which adolescents (M age=15.5, SD=1.2) were assigned to a brief cognitive behavioral prevention program or an educational brochure control condition, we tested whether elevated motivation to reduce depression and initial depressive symptom severity amplified intervention effects and whether negative life events, social support deficits, and substance use attenuated intervention effects. Hierarchical linear modeling (HLM) indicated differential intervention effects for two of the five examined variables: negative life events and substance use. For adolescents at low and medium levels of substance use or negative life events, the CB intervention produced declines in depressive symptoms relative to controls. However, at high levels of substance use or negative life events, the CB intervention did not significantly reduce depressive symptoms in comparison to controls. Results imply that high-risk adolescents with either high rates of major life stress or initial substance use may require specialized depression prevention efforts.