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Psychoactive substance use among children in Afghanistan is an issue of concern. Somewhere around 300,000 children in the country have been exposed to opioids that either parents directly provided to them or by passive exposure. Evidence-based and culturally appropriate drug prevention and treatment programs are needed for children and families. The goals of this study were to: (1) examine lifetime psychoactive substance use in girls and boys at treatment entry; and (2) examine differential changes in substance use during and following treatment between girls and boys. Children ages 10-17 years old entering residential treatment were administered the Alcohol, Smoking and Substance Involvement Screening Test for Youth (ASSIST-Y) at pre- and post-treatment, and at three-month follow-up. Residential treatment was 45 days for children and 180 days for adolescents and consisted of a comprehensive psychosocial intervention that included education, life skills, individual and group counseling and, for older adolescents, vocational skills such as embroidery and tailoring. Girls and boys were significantly different regarding lifetime use of five substances at treatment entry, with girls less likely than boys to have used tobacco, cannabis, stimulants, and alcohol, and girls more likely than boys to have used sedatives. Differences between boys and girls were found for past-three-month use of four substances at treatment entry, with girls entering treatment with higher past-three-month use of opioids and sedatives, and boys with higher past-three-month use of tobacco, cannabis, and alcohol. Change over the course of treatment showed a general decline for both girls and boys in the use of these substances. Girls and boys in Afghanistan come to treatment with different substance use histories and differences in past-three-month use. Treatment of children for substance use problems must be sensitive to possible differences between girls and boys in substance use history., Competing Interests: Competing interests. The authors declare that there is no conflict of interest regarding the publication of this paper.