Researchers have found that adolescents who identify as gay, lesbian, or bisexual (GLB) are at higher risk for increased substance use and mental health symptoms. The current study is a secondary analysis of two clinical trials for street-living youth. This analysis examines self-identification as GLB as a moderator of treatment effects and addresses whether street-living GLB youth respond differently to a therapeutic intervention than non-GLB street-living youth. Comparisons were made of treatment outcomes on two categories of variables (drug use and mental health symptoms) among 244 homeless GLB and non-GLB identified adolescents. Overall, GLB and non-GLB adolescents showed similar reductions in drug use and mental health symptoms. However, compared to non-GLB adolescents, GLB adolescents showed greater improvement in reduction of drug use and internalizing and depressive symptoms scores. While both groups reported less drug use and fewer mental health symptoms from baseline to post-intervention, GLB youth's scores improved more drastically. Implications of using the identified treatment intervention are discussed.