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To test whether a social network tailored substance abuse prevention program can reduce substance use among high-risk adolescents without creating deviancy training (iatrogenic effects).A classroom randomized controlled trial comparing control classes with those receiving an evidence-based substance use prevention program [Towards No Drug Abuse (TND)] and TND Network, a peer-led interactive version of TND. Students (n = 541, mean age 16.3 years) in 75 classes from 14 alternative high schools completed surveys before and approximately 1 year after curriculum delivery. Past-month use of tobacco, alcohol, marijuana and cocaine were assessed.Overall, TND Network was effective in reducing substance use. However, the program effect interacted with peer influence and was effective mainly for students who had peer networks that did not use substances. Students with classroom friends who use substances were more likely to increase their use.A peer-led interactive substance abuse prevention program can accelerate peer influences. For students with a peer environment that supports non-use, the program was effective and reduced substance use. For students with a peer environment that supports substance use, an interactive program may have deleterious effects.