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Substance abuse among school students may lead to criminal penalty in addition to possible physical, social, and psychological harm. Psychosocial intervention programs in schools focus on children’s social and academic skills, including enhancing peer relationships, self-control, coping skills, social behaviors, and drug offer refusal skills. Aim: to develop Psychosocial intervention program for school students for protection against substance abuse. Study design: a quasi-experimental design was utilized to conduct this study. Setting: this study was conducted at two schools: school for males (El-Tabri Preparatory School) and school for female (The New Heliopolis Preparatory) at Cairo city. Subject: convenient sample of 262 students were recruited for conducting this study. Data collection tools: 1) Socio-demographic questionnaire for students. 2) Knowledge and attitude about substance abuse. 3) Self Concept Scale. Results: the present study revealed that there was a highly statistically significant improvement regarding knowledge and attitude scores post implementation of psycho social intervention program. In addition, there were highly statistically significant positive correlations between knowledge and attitude of studied students. Conclusion: the implementation of psychosocial intervention program has a statistically significant positive effect on students knowledge and attitude concerning substance abuse. Recommendations: The developed program should be implemented on a wider scale in the study settings and in similar ones to confirm its positive effects and improvement. Future programs should include the parents of adolescents to teach them how to deal with their adolescents and to avoid risky behavior that may occur at this age.