Abstract: Background: Contemporary intervention models use research about the determinants of adolescent problems and their course of symptom development to design targeted interventions. Because developmental detours begin frequently during early-mid adolescence, specialized interventions that target known risk and protective factors in this period are needed. Methods: This study (n = 83) examined parenting practices as mediators of treatment effects in an early-intervention trial comparing Multidimensional Family Therapy (MDFT), and a peer group intervention. Participants were clinically referred, low-income, predominantly ethnic minority adolescents (average age 14). Assessments were conducted at intake, and six weeks after intake, discharge, and at 6 and 12 months following intake. Results: Previous studies demonstrated that MDFT was more effective than active treatments as well as services as usual in decreasing substance use and improving abstinence rates. The current study demonstrated that MDFT improves parental monitoring—a fundamental treatment target—to a greater extent than group therapy, and these improvements occur during the period of active intervention, satisfying state-ofthe- science criteria for assessing mediation in randomized clinical trials. Conclusions and Scientific Significance: Findings indicate that change in MDFT occurs through improvements in parenting practices. These results set the foundation for examining family factors as mediators in other samples.