Objective: School-level use of tobacco and alcohol are related to individual students' use in high school, but few studies have examined the effects of school-level substance use in early adolescence. In addition, little is known about factors modifying individuals' vulnerability to school-level influences. This study examined school-wide levels of alcohol, cigarette, and marijuana use in relation to early adolescents' substance use and the role of peer deviance and parenting practices as modifiers of school-level effects. Method: This cross-sectional study included 542 students attending 49 public middle schools in a single metropolitan area. Students reported on their use of alcohol, cigarettes, and marijuana, and friends' deviant behavior in the last 12 months. Parents provided information about parental nurturance and harsh and inconsistent discipline. School-wide levels of substance use were obtained from the Pride Surveys completed by all students in Grades 6-8 at each school. Multilevel logistic regressions modeled individual use as a function of school-level use for each substance. Interactions of friends' deviance and poor parenting with school-level substance use evaluated differential susceptibility. Results: Among the three substances, only school-level rates of cigarette smoking were associated with individual smoking. The relationships of school-level smoking and alcohol use with individual use were stronger for students whose parents reported poorer parenting practices. Conclusions: Antismoking programs may need to preferentially target middle schools with high rates of cigarette smoking. Students who receive suboptimal parenting may benefit from increased support to deter them from early initiation of smoking and alcohol use, especially in high-risk schools.