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Transgender youth face tremendous stress stemming from having stigmatized gender identities and expressions. In an effort to cope, transgender youth may engage in substance use. For decades, scholars have examined how a positive school climate can support the well-being of youth facing adversity. This study is one of the first studies to examine associations between school climate (school connection and school adult support) and past-30 day and in-school substance use in a large, statewide sample of transgender youth. The results indicate that school connection and school adult support are associated with a lower likelihood of alcohol, cigarette, marijuana, and illicit drug use among transgender youth. The study results help inform current school-based efforts aimed at supporting transgender youth.