BackgroundWe describe the initial results of an adult academic emergency department (ED) nontargeted hepatitis C virus (HCV) screening program serving Appalachia, which is disproportionately affected by the opioid epidemic.MethodsThe study was a retrospective screening study of ED systematic, nontargeted, opt-out HCV testing outcomes from July 2018 through September 2020. Eligibility requirements for “nontargeted” HCV testing included age ≥18 years, verbally able to communicate, receiving bloodwork already as part of routine clinical care, and not opting out of testing. For eligible individuals who did not opt out of testing, an HCV antibody (Ab) test was performed. Reactive Ab tests were confirmed with reflexive HCV RNA testing. The primary study outcome was the characterization of HCV Ab and RNA prevalence.ResultsThere were 75 722 unique adult visitors during the period studied. Of these, 54 931 individuals were verbally engaged regarding testing and did not opt out. A total of 34 848 individuals received HCV Ab testing, with 3665 patients (10.5%) having reactive results. RNA confirmatory testing was reflexively performed in all Ab-positive patients, with 1601 (50.3%) positive. The majority of HCV Ab– and RNA-positive patients were young, born after 1965, and were more likely to be White, male, Medicaid insured, and report a history of injection drug use.ConclusionsED nontargeted, opt-out testing can identify a high prevalence of HCV infection among adult visitors. HCV infection was disproportionately high among younger, White individuals, likely reflecting the escalating syndemic of opioid injection and HCV transmission in Appalachia.