The purpose of this study was to assess the combined effectiveness of a parenting intervention, Families Preparing the New Generation (FPNG), and a youth curriculum, keepin ' it REAL (kiR), on substance use prevention for middle school students in a large urban metro area of the Southwest USA. The study aimed to generate usable knowledge on what works in adolescent substance use prevention and how it works best-a combined parent and youth programing or parent-only programming. A total of 532 adolescents in the 7th grade from 19 participating middle schools were randomly assigned into three intervention conditions: Parent-Youth (PY), Parent-Only (PO), and Comparison (C). This article focuses on the comparison between PY and PO in order to determine which intervention strategy works best to reduce adolescent substance use including, alcohol, inhalant, cigarette, and marijuana uses. A generalized estimating equation (GEE) model examined the longitudinal data. The results for alcohol use show that PO yielded better results than PY and that PY outperformed C after 20 months. Further, PO showed a decreasing trajectory in any substance use over time since the implementation of the intervention. The effect sizes based on Cohen's h indicate small effects in any substance use and alcohol use for PO condition and smaller effects for the PY condition. These findings have implications for the design of future culturally specific parenting and youth prevention interventions with Latino families.