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Examination of differences between primary alcohol and drug abusing adolescents can provide valuable direction to intervention efforts, though little research in this area has been conducted. The current study compared primary alcohol and primary drug abusing runaway adolescents who were randomly assigned to family therapy or treatment as usual. Baseline differences, as well as response to treatment, were examined separately for alcohol and drug use and by gender. Although few baseline differences were found, hierarchical linear modeling indicated that alcohol and drug abusing male and female adolescents responded differently to therapy. Primary drug using males showed poorer alcohol use outcomes than did primary alcohol abusers. Specifically, alcohol use increased for primary drug using males receiving family therapy, while drug use decreased in all groups. Findings suggest that alcohol and drug use outcomes might be improved at treatment planning through consideration of client’s gender and primary alcohol versus drug use. D 2006 Elsevier Ltd. All rights reserved.