Youth violence is a critical public health problem across races/ethnicities in the United States. Although the differential association between substance use and physical aggression has been empirically proven, no tests have assessed the moderating effects of sociocultural differences in such associations. The purpose of this study is to test the moderating impact of race/ethnicity-as an indicator of sociocultural differences--on the associations between substance use and adolescent aggression, by conducting a validity assessment of a physical aggression measure for high school students with emphasis on Hispanics and other minorities. A cross-sectional, secondary data analysis of the 2007 national Youth Risk Behavior Survey, with a representative sample of all U.S. high school students, was conducted. Contingency table and chi-square test evaluated the statistical relationship between substance use (alcohol, marijuana, either, or both) and self-reports of physical aggression, race/ethnicity, age, and sex of the respondent. Three logistic regression analyses assessed the effect of race/ethnicity on the likelihood of reporting physical aggression by overall substance use and type of substance use. Statistical significant associations were found between physical aggression and alcohol and/or marijuana use. The self-report of substance use (marijuana or alcohol) and alcohol use significantly increased the likelihood of physical aggression across races/ethnicities, highest among racial/ethnic minorities (Blacks > Hispanic > Others > Whites). The differential impact of substance use on physical aggression was confirmed, and such impact was moderated by the sociocultural context (race/ethnicity) of the adolescent. In-depth validity assessments are needed to confirm this study's predictive validity findings.