A brief motivational intervention with 117 homeless adolescents was evaluated using a randomized design and 3-month follow-up. The intervention was designed to raise youths' concerns about their substance use, support harm reduction, and encourage greater service utilization at a collaborating agency. The study was designed to strengthen initial promising results of an earlier study (P. L. Peterson, J. S. Baer, E. A. Wells, J. A. Ginzler, & S. B. Garrett, 2006). Several modifications in the clinical protocol were included to enhance engagement with the intervention. Analyses revealed no significant benefits for intervention participants when homeless youths' substance use rates were compared with those of control participants. Service utilization during the intervention period increased for those receiving the intervention but returned to baseline levels at follow-up. Participants reported overall reductions in substance use over time. Differences between sampling methods for the current and previous study are discussed, as are the limitations of brief interventions with this population. Future research needs to elucidate mechanisms of change and service engagement for highly vulnerable youth.