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OBJECTIVE: Motivational interviewing (MI) is a promising intervention for helping patients with mental health problems reduce their substance use. Examining the cost-effectiveness of MI and associations between MI and the use of health services can inform appropriate intervention strategies for these patients. METHOD: Kaiser Permanente adult patients with depression symptoms (Patient Health Questionnaire [PHQ-9] score > 5) seen in outpatient psychiatry (N = 302) who reported unhealthy alcohol use or other substance use (primarily cannabis) were randomized to three sessions of MI (intervention) or printed literature (control) with telephone follow-up interviews at 6 and 12 months. Cost-effectiveness analyses compared intervention costs associated with 30-day abstinence from unhealthy alcohol use (i.e., any days of ≥4/≥5 drinks for women/men) and cannabis use. Multivariable analyses examined associations between MI and healthcare utilization at 12 months (emergency department, primary care, psychiatry, and addiction treatment). RESULTS: MI resulted in greater likelihood of abstaining from unhealthy alcohol use (70.0% vs. 60.2%, p < .01) and cannabis use (74.6% vs. 63.9%, p < .01) than the control at 6 months, but outcomes did not differ at 12 months. The 6-month incremental cost-effectiveness ratios were $1,207-$1,523 per abstinent patient for unhealthy drinking and $1,040-$1,313 per abstinent patient for cannabis. There were no differences between groups on health service utilization. CONCLUSIONS: MI cost more than the control condition but yielded better outcomes at 6 months; MI had no relationship to health service utilization. Findings can inform implementation of substance use interventions through understanding MIs potential clinical and cost impact and its relationship to health services use.