Background: School administrators and teachers face difficult decisions about how best to use school resources to meet academic achievement goals. Many are hesitant to adopt prevention curricula that are not focused directly on academic achievement. Yet, some have hypothesized that prevention curricula can remove barriers to learning and, thus, promote achievement. We examined relationships among school levels of student substance use and risk and protective factors that predict adolescent problem behaviors and achievement test performance. Methods: Hierarchical generalized linear models were used to predict associations involving school-averaged levels of substance use and risk and protective factors and students' likelihood of meeting achievement test standards on the Washington Assessment of Student Learning, statistically controlling for demographic and economic factors known to be associated with achievement. Results: Levels of substance use and risk/protective factors predicted the academic test score performance of students. Many of these effects remained significant even after controlling for model covariates. Conclusions: Implementing prevention programs that target empirically identified risk and protective factors has the potential to have a favorable effect on students' academic achievement.