This study used data from a sample of 6th to 12th grade students (N = 48,641, 51% female), nested in 192 schools, to determine if the influence of family-based protective factors varied across different school contexts. Hierarchical logistic regression models were used to examine the effects of individual-level family protective factors, relative to school-level aggregates of the same factors, on recent (past 30 days) use of cigarettes, alcohol, and marijuana. Cross-level interactions indicated that the effect of the student's level of family protection, relative to other students in their school, differed depending on the aggregated school level of family protection. The results suggested that the benefit of belonging to a well-functioning family was more influential for students attending schools characterized by higher-than-average aggregated levels of protection compared to students attending schools of lower-than-average protection. Thus, family-level factors offered less protection for students in relatively high-risk school contexts. These results were consistent with a protective-reactive interaction and suggest that a thorough understanding of adolescent substance use must consider the complex interplay among adolescents, their families, and their social environments.