Substance use among adolescents is a complex problem and an ongoing concern. Literature has identified a critical need to understand the role that schools can play in preventing adolescent substance use. Adopting an ecological perspective, we used multigroup logistic regression to determine the influence of school support and school meaningful participation on substance use among male and female adolescents after controlling for ethnicity, home, peer, community, and internal factors. A random sample of students in 9th and 11th grade was selected for each substance use group (abstainer, user, and polyuser; 7,642 participants) from the California Healthy Kids Survey. Results suggest that for males, perceived school support was related to significantly lower odds of belonging to the polyuser group. For females, family and peer factors largely accounted for influences on substance use. Findings bring focus to alterable factors that school professionals can influence that are associated with adolescent substance use. (Contains 3 tables.)