Objectives: Alcohol, tobacco, and other drug use are important problems that typically begin during adolescence.Fortunately substantial progress has been made in developing effective drug abuse prevention programs for youth over the past two decades. The Life Skills Training (LST) program is an effective primary prevention program for adolescent drug abuse that addresses the risk and protective factors associated with drug use initiation and teach skills related to social resistance and enhancing social and personal competence. The Life Skills Training (LST) program is a multi-component competence enhancement based preventive intervention that emphasizes drug resistance skills training within the context of a generic personal and social skills training mode The LST program is one of the most thoroughly evaluated evidence-based drug abuse prevention programs for middle school students. The LST prevention program consists of three major components. The first component is designed to teach students a set of general self-management skills, and the second focuses on general social skills. These two components are designed to enhance personal and social competence and to decrease motivations to use drugs and vulnerability to social influences that support drug use. The third component of LST focuses on information and skills that are specific to drug use in order to promote drug resistance skills, antidrug attitudes, and antidrug normsThe purpose of this study was to assess the effect of life skills training intervention on risk and protective factors of alcohol, tobacco, and other drug use among high-risk youths of Tehran city. Method: A sample of 75 high risk students of inner city school, 35 students as an experimental group and 35 matched students as a control group was participated in the study. While the students from the control group received no specific intervention, the students in the experimental group participated in the life skills training intervention which consisted of 10 sessions. The programme was conducted by trained school counselor. All of the subjects completed Anonymous risk and protective factors and current drug use (4-week prevalence) questionnaires pre and post intervention. Findings: Results of study indicated that The Life Skills Training (LST) program had a positive and significant effect on individual risk and protective factors such as self-concept, self-management, social and assertiveness skills, and attitude about drug abuse. Students who received the life skills training program reported less intention and desire for Alcohol, tobacco, and other drug use and increased anti-drug Attitudes relative to control group who did not receive the intervention. However, the program did not have a statistically significant effect on social risk factors and current use (4-week prevalence) of alcohol, tobacco, and other drug. Results: Many prevention studies focus on the efficacy of a particular prevention approach in terms of its impact on alcohol, tobacco, and other drug use. However, there is an increasing recognition of the need to examine program effects on hypothesized mediating variables and the extent to which changes in these variables lead to changes in drug use behavior. A focus on mediating mechanisms in evaluation studies is important because it can identify the “active ingredients” in existing prevention programs, inform ways to refine existing programs, and provide new information to guide future prevention program development. Findings of this utudy show that the life skills training program as a universal prevention program that originally designed for general adolescent populations is effective in a sample of high risk adolescents. These findings provide evidence for the mediating mechanisms through which competence skills protect young people from drug abuse and potential mechanisms through which the Life Skills Training program is effective, and also provided a strong support for the social influence and competence enhancement model of alcohol, tobacco, and other drug use prevention. Life Skills Training program is competence enhancement approaches to prevention, that applicable to multiple substances and multiple problem behaviors because it is designed to teach life skills and enhance general competence, teaching the kind of skills for coping with life that will have a relatively broad application.