OBJECTIVE The purpose of this study was to compare the relative effectiveness of three treatment modalities for adolescent substance use: biological drug screening (BDS), Motivational Enhancement Therapy-Cognitive Behavioral Therapy (MET/CBT5), and BDS combined with MET/CBT5, relative to no treatment. METHOD This study comprised 5,186 adolescents (70% male) enrolled in substance use treatment and tracked through the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment's database (BDS = 1,110; MET/CBT5 = 784; BDS combined with MET/CBT5 = 2,539; no treatment = 753). Outcomes of interest were substance use frequency and severity of substance use problems at 3, 6, and 12 months, as measured by the Global Appraisal of Individual Needs survey. Propensity score weighting was used to adjust for pretreatment covariate imbalances between groups. Weighted generalized linear models were used to estimate the impact of treatment on outcomes at 3, 6, and 12 months. RESULTS BDS, alone or in combination with MET/CBT5, was associated with improved substance use and substance problems outcomes. Relative to youth reporting no treatment services, the BDS group reported significantly lower substance use at all visits, with the observed difference increasing over time. BDS alone was associated with significantly fewer substance problems than bds combined with met/cbt5 at all visits and significantly lower use at 12 months. CONCLUSIONS Our results demonstrate significant improvement on substance use outcomes associated with BDS and offer preliminary evidence that BDS, particularly standalone BDS, may be an effective form of drug treatment for adolescents. Further work, including randomized studies, should explore the optimal format of administering BDS to adolescents to achieve maximum effectiveness.