This study tested a mediation model of the relationship with school problems, social network quality, and substance use with a primary care sample of 301 urban adolescents. It was theorized that social network quality (level of risk or protection in network) would mediate the effects of school problems, accounting for internalizing problems and relations with parents, on substance use. Results of path modeling with AMOS showed that the model provided a very good fit to the data and demonstrated partial mediation effects of social network quality on substance use. The standardized mediated effect of school problems on substance use, mediated by social network quality, was 0.13 (p less than 0.01, 95% CI [0.072, 0.189]). An effect size measure was applied to determine what proportion of the total effect was mediated by the intervening (social network quality) variable and produced a 0.34 effect size. The results highlight the potential preventive role of social network quality in addressing urban adolescent substance use.