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BACKGROUND & AIMS: Direct-acting antivirals (DAA) have revolutionized the management of hepatitis C virus (HCV) infection. Data on national inpatient mortality in this new era are scarce. This study aimed to evaluate inpatient mortality among HCV-related hospital stays in the United States (US) during the years DAA were available. METHODS: We conducted a cross-sectional analysis of the National Inpatient Sample (NIS) between 2012 and 2016. Using discharge weights, national estimates of HCV-related hospitalizations were calculated. Simple and multiple logistic regressions were performed to identify factors associated with inpatient mortality. RESULTS: A total of 67,630 hospitalizations from NIS were HCV-related, accounting for an estimated 338,150 hospitalizations during 2012 – 2016. These hospitalizations have estimated average annual total charges of $4.6 billion, adjusted to 2020 US dollars. The rate of inpatient mortality declined modestly from 5.25% in 2012 to 4.75% in 2016 (P=0.07). Over the 5-year study period, the proportion of in-hospital deaths increased for black patients, Medicaid beneficiaries, and patients with substance-related disorders. Controlling for known predictors, the odds of inpatient mortality were significantly greater among black patients compared to white patients (OR= 1.27 [95% CI=1.16 – 1.39]). CONCLUSIONS: The burden of HCV infection is substantial given the disease is now curable. Our findings indicate that major disparities in the HCV disease burden exist in the era of DAA.