The prevalence of substance abuse among adolescents from low- and middle-income countries is increasing drastically and requires immediate intervention. The objective of this longitudinal quasi-experimental panel study was to design and implement a skill-based intervention to prevent and reduce substance use among urban adolescents who attended 2 randomly selected high-schools in Tehran, Iran. One-year post intervention data show that substance abuse, knowledge, attitudes, peer resistance skills, level of self-control, self-efficacy, and perceived susceptibility among intervention group were significantly improved, whereas level of self control and attitudes against substance abuse among the control group deteriorated. To efficiently prevent substance abuse among youth primary preventive interventions should be implemented before onset of substance abuse to improve resistance skills and provide adolescents with information and skills needed to develop anti-drug norms. (Contains 4 tables.)