The present study tested the effectiveness of a substance abuse prevention program for deterring tobacco, alcohol, and marijuana use among high school students. The prevention program teaches social resistance skills and general personal and social competence skills. Rates of substance use behavior were examined among students (N = 452) from 12 public high schools that were randomly assigned to either receive the prevention program (5 schools, n = 196) or serve as a treatment-as-usual control group (7 schools, n = 256). The impact of the prevention program was tested using composite indicators of daily substance use based on items measuring the frequency of smoking, drinking, drunkenness, marijuana use, and marijuana intoxication. Data were analyzed using generalized estimating equations to adjust for school-level clustering. Comparison of the posttest adjusted means (controlling for school clustering, gender, race/ethnicity, and family structure) revealed that the intervention produced significant prevention effects on daily substance use, both in terms of a daily polysubstance use index and the proportion of daily substance users across experimental condition. Findings indicated that there were 52% fewer daily substance users in the intervention condition compared to controls. Conclusions drawn from this study are that: (1) daily substance use can be prevented in high school students using a competence enhancement approach that addresses key risk and protective factors; (2) prevention approaches that are effective for middle school students can also be effective for high school students, if adapted to be developmentally appropriate; and (3) universal prevention approaches delivered by classroom teachers with minimal specialized training offer the potential for widespread dissemination and a cost-effective approach to an important public health problem.