Objective: This study examined the efficacy of Motivational Interviewing (MI) to reduce hazardous drinking and drug use among adults in treatment for depression. Method: Randomized controlled trial based in a large outpatient psychiatry program in an integrated health care system in Northern California. The sample consisted of 307 participants ages 18 and over who reported hazardous drinking, drug use (primarily cannabis) or misuse of prescription drugs in the prior 30 days, and who scored ≥5 on the Patient Health Questionnaire (PHQ-9). Participants were randomized to receive either 3 sessions of MI (1 in person and 2 by phone) or printed literature about alcohol and drug use risks (control), as an adjunct to usual outpatient depression care. Measures included alcohol and drug use in the prior 30 days and PHQ-9 depression symptoms. Participants completed baseline in-person interviews and telephone follow-up interviews at 3 and 6 months (96 and 98% of the baseline sample, respectively). Electronic health records were used to measure usual care. Results: At 6 months, MI was more effective than control in reducing rate of cannabis use (p = .037); and hazardous drinking (≥4 drinks in a day for women, ≥5 drinks in a day for men; p = .060). In logistic regression, assignment to MI predicted lower cannabis use at 6 months (p = .016) after controlling for covariates. Depression improved in both conditions. Conclusions: MI can be an effective intervention for cannabis use and hazardous drinking among patients with depression.