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This study examines the role of school-climate with relation to recent substance use and in-school substance use for LGB homeless and non-homeless students (n=31,538). Bivariate and multivariate analyses were conducted to examine the relationship between school climate (school connectedness and caring relationships) and past-30-day and in-school use of cigarettes, alcohol, marijuana, inhalants, prescription pain medication and other illegal drugs, for LGB homeless and non-homeless students. The results indicated that school connectedness and school adult support moderated the relationship between homelessness and some substance use indicators. The results indicate that a positive school-climate may serve as a protective factor for LGB homeless students and highlight the need for substance use prevention interventions that integrate school connectedness and supportive relationships in school.