Studies document that there are efficacious interventions to prevent adolescent depression and internalizing symptoms, including several family-focused interventions. Questions remain about for whom interventions work (moderation) and by what mechanisms they work (mediation) to prevent internalizing symptoms. Unfortunately, single trials are often underpowered to address moderation and mediation, an issue addressed in this paper. This synthesis study combined individual-level, longitudinal data from 721 adolescents across 3 randomized clinical trials of Familias Unidas, a family-focused prevention intervention for Hispanic youth. Using integrative data analysis (IDA) methods applied to trials, the study examined intervention moderation and mediation effects on internalizing symptoms. Baseline internalizing symptoms were a significant moderator of the intervention's effects on internalizing symptoms, while baseline externalizing symptoms did not moderate intervention effects. Baseline parent-adolescent communication, a modifiable risk factor and hypothesized mechanism by which the intervention works, significantly moderated the intervention's effects. Specifically, the intervention was more efficacious in its impact on internalizing symptoms for youth with lower initial levels of parent-adolescent communication compared to those with higher communication levels. Moderated mediation analyses showed that parent-adolescent communication changes mediated the intervention's effects on internalizing symptoms, with stronger effects for those with poorer baseline communication. Results suggest a potential benefit of identifying youth risks prior to interventions, and targeting specific modifiable mediators that lead to reductions of internalizing problems of adolescents. Findings also highlight advantages of utilizing data from combined trials and IDA for examining intervention moderators and mediators.