Substance use among adolescents with one or more psychiatric disorders is a significant public health concern. In this study, 151 psychiatrically hospitalized adolescents, ages 13-17 with comorbid psychiatric and substance use disorders, were randomized to a two-session Motivational Interviewing intervention to reduce substance use plus treatment as usual (MI) vs. treatment as usual only (TAU). Results indicated that the MI group had a longer latency to first use of any substance following hospital discharge relative to TAU (36 days versus 11 days). Adolescents who received MI also reported less total use of substances and less use of marijuana during the first 6 months post-discharge, although this effect was not significant across 12 months. Finally, MI was associated with a significant reduction in rule-breaking behaviors at 6-month follow-up. Future directions are discussed, including means of extending effects beyond 6 months and dissemination of the intervention to community-based settings.