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Abstract Substance use disorders (SUDs) commonly co-occur with mental illness. However, the ongoing addiction crisis raises the question of how opioid use disorder (OUD) impacts healthcare utilization relative to other SUDs. This study examines the utilization patterns of patients with major depressive disorder (MDD) and: (1) co-occurring OUD (MDD-OUD); (2) a co-occurring SUD other than OUD (MDD-NOUD); and (3) no co-occurring SUD (MDD-NSUD). We analyzed electronic health records (EHRs) derived from multiple health systems across the New York City (NYC) metropolitan area between January 2008 and December 2017. 11,275 patients aged ≥18 years with a gap of 30–180 days between 2 consecutive MDD diagnoses and an antidepressant prescribed 0–180 days after any MDD diagnosis were selected, and prevalence of any SUD was 24%. Individuals were stratified into comparison groups and matched on age, gender, and select underlying comorbidities. Prevalence rates and encounter frequencies were measured and compared across outpatient, inpatient, and emergency department (ED) settings. Our key findings showed that relative to other co-occurring SUDs, OUD was associated with larger increases in the rates and odds of using substance-use-related services in all settings, as well as services that integrate mental health and substance abuse treatments in inpatient and ED settings. OUD was also associated with larger increases in total encounters across all settings. These findings and our proposed policy recommendations could inform efforts towards targeted OUD interventions, particularly for individuals with underlying mental illness whose treatment and recovery are often more challenging.