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Heart Failure (HF) and Opioid Use Disorder (OUD) independently have significant impact on patients and the United States (US) health system. In the setting of the opioid epidemic, research on the effects of OUD on cardiovascular diseases is rapidly evolving. However, no study exists on differential outcomes of ischemic cardiomyopathy (ICM) and nonischemic cardiomyopathy (NICM) in patients with HF with OUD. We performed a retrospective, observational cohort study using National Inpatient Sample (NIS) 2018-2020 databases. Patients aged 18 years and above with diagnoses of HF with concomitant OUD were included. Patients were further classified into ICM and NICM. Primary outcome of interest was differences in all- cause in-hospital mortality. Secondary outcome was incidence of cardiogenic shock. We identified 99,810 hospitalizations that met inclusion criteria, ICM accounted for 27%. Mean age for ICM was higher compared to NICM (63 years vs 56 years, P < 0.01). Compared to NICM, patients with ICM had higher cardiovascular disease risk factors and comorbidities; type 2 diabetes mellitus (46.3 % vs 30.1%, P < 0.01), atrial fibrillation/flutter (33.5% vs 29.9%, P < 0.01), hyperlipidemia (52.5% vs 28.9%, P < 0.01), and Charlson comorbidity index ≥5 was 46.7% versus 29.7%, P < 0.01. After controlling for covariates and potential confounders, we observed higher odds of all-cause in-hospital mortality in patients with NICM (aOR = 1.36; 95% CI:1.03-1.78, P = 0.02). There was no statistical significant difference in incidence of cardiogenic shock between ICM and NICM (aOR = 0.86;95% CI 0.70-1.07, P = 0.18). In patients with HF with concomitant OUD, we found a 36% increase in odds of all-cause in-hospital mortality in patients with NICM compared to ICM despite being younger in age with less comorbidities. There was no difference in odds of in-hospital cardiogenic shock in this study population. This study contributes to the discussion of OUD and cardiovascular diseases which is rapidly developing and requires further prospective studies., (Copyright © 2023 Elsevier Inc. All rights reserved.)