Background: The physical environment influences adolescent health behavior and personal development. This article examines the relationship between level of school disrepair and substance use among students attending regular high school (RHS) and alternative high school (AHS). Methods: Data were collected from students (N = 7058) participating in 2 randomized controlled trials of a school-based substance abuse prevention program implemented across the United States. Students provided substance use and demographic information on a self-reported survey. Data for the physical disrepair of schools were collected from individual rater observations of each school environment. We hypothesized that school disrepair would be positively associated with substance use controlling for individual characteristics and a socioeconomic status proxy. Multilevel mixed modeling was used to test the hypothesized association and accounted for students nested within schools. Results: Findings indicated that students attending AHS with greater school disrepair were more likely to report the use of marijuana and other illicit drugs (ie, cocaine, heroin). Students attending RHS with greater school disrepair were less likely to report smoking cigarettes. Conclusions: Differences in findings between RHS and AHS students are discussed, and implications for substance use prevention programming are offered. Students attending AHS with greater school disrepair may require more substance abuse prevention programming, particularly to prevent illicit substance use. (Contains 5 tables.)