We evaluated the impact of implementing automated hepatitis C (HCV) opt-out screening in the emergency department of an urban, academic medical center with high HCV prevalence, in the context of a longstanding HCV opt-in screening model. We compared nine-month periods before and after implementation. HCV testing increased by 502%, and active HCV infection identification increased by 212%. Settings where there is great opportunity for HCV diagnosis, such as emergency department settings, should consider opt-out HCV screening models. (Am J Public Health. 2024;114(11):1228-1231. https://doi.org/10.2105/AJPH.2024.307783).