This randomized trial of a family-focused preventive intervention for Mexican American middle schoolers examined internalizing, externalizing, and substance use outcomes in late adolescence, 5 years after completing the intervention. Parent-adolescent conflict was tested as a mediator of these effects. The role of parent and adolescent acculturation in these pathways was also examined. There were 494 seventh-grade adolescents and their primary female caregivers randomized to receive either a 9-week multicomponent intervention or a brief workshop control group. Assessments were conducted at pretest, 2-year follow-up (9th grade), and 5-year follow-up (when most participants were in the 12th grade). The Bridges program significantly reduced mother-adolescent conflict measured in the 9th grade, with conflict mediating program effects on internalizing and externalizing symptoms, adolescent substance use, and diagnosed internalizing disorder in late adolescence. Mother and child acculturation were both significantly predictive of late adolescence outcomes. Contrary to hypotheses, neither mother nor child acculturation emerged as a significant predictor of mother-adolescent conflict, and the interaction of mother and adolescent acculturation was similarly not related to mother-adolescent conflict. Intervention effects were largely consistent across different levels of acculturation. These findings provide support for the efficacy of family-focused intervention during early adolescence, both in reducing mental health problems and substance use in the long term and in impacting parent-adolescent conflict processes that appear to play an important role in the development of later adjustment problems.