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Background: Social capital (SC) is one of the most important assets and a vital determinant of sustainabledevelopment of any country. The aim of this study was to determine the prevalence and the relationshipbetween SC and substance use (SU) in Southeast Iranian adolescents.Methods: This cross-sectional study was conducted among high school students in three cities located in southeast of Iran. We recruited 600 adolescents (329 girls and 271 boys) through multistage sampling duringSeptember to November 2018. The data collection instrument was a self-administered standardizedquestionnaire that included basic demographic characteristics, SC constructs items, and questions about SUbehavior in the participants.Findings: The mean SC score among boys and girls studied was 3.46 and 3.33, respectively (from 5 score).Among the SC constructs, respectively, the lowest and highest score belonged to social trust and [2.84 in girlsand 2.98 in boys with 95% confidence interval (CI) of 0.06-0.21, P < 0.001] and bonding to family (3.92 ingirls and 4.25 in boys with 95% CI of 0.22-0.44, P < 0.001). The ever use prevalence of at least one substanceabuse was 55.9% (n = 181) for boys and 36.6% (n = 68) for girls. Hookah (41.8%) and alcohol (16.9%) were themost substances abused by participants. One-point increase in score of the constructs of social participation,social cohesion, bonding with family, and bonding with schools was associated with a reduce of 17%, 22%, 26%,and 46% in the probability of ever SU, respectively.Conclusion: There was a strong relationship between SU and SC. Thus, rising SC as an effective communitybased and indirect approach can help policy makers and professionals in preventing SU in Iran. However, priorto any intervention, identification of more causality may be required