Recent research has identified high hepatitis C virus (HCV) prevalence among older U.S. residents who contracted HCV decades ago and may no longer be recognized as high risk. We assessed the cost-effectiveness of screening 100% of U.S. residents born 1946-1970 over 5 years (birth-cohort screening), compared with current risk-based screening, by projecting costs and outcomes of screening over the remaining lifetime of this birth cohort. A Markov model of the natural history of HCV was developed using data synthesized from surveillance data, published literature, expert opinion, and other secondary sources. We assumed eligible patients were treated with pegylated interferon plus ribavirin, with genotype 1 patients receiving a direct-acting antiviral in combination. The target population is U.S. residents born 1946-1970 with no previous HCV diagnosis. Among the estimated 102 million (1.6 million chronically HCV infected) eligible for screening, birth-cohort screening leads to 84,000 fewer cases of decompensated cirrhosis, 46,000 fewer cases of hepatocellular carcinoma, 10,000 fewer liver transplants, and 78,000 fewer HCV-related deaths. Birth-cohort screening leads to higher overall costs than risk-based screening (80.4billionversus53.7 billion), but yields lower costs related to advanced liver disease (31.2billionversus39.8 billion); birth-cohort screening produces an incremental costeffectiveness ratio (ICER) of 37,700perqualityβadjustedlifeyeargainedversusriskbasedscreening.SensitivityanalysesshowedthatreducingthetimehorizonduringwhichhealthandeconomicconsequencesareevaluatedincreasestheICER;similarly,decreasingthetreatmentratesandefficacyincreasestheICER.Modelresultswererelativelyinsensitivetootherinputs.Conclusion:BirthβcohortscreeningforHCVislikelytoprovideimportanthealthbenefitsbyreducinglifetimecasesofadvancedliverdiseaseandHCVβrelateddeathsandiscostβeffectiveatconventionalwillingnessβtopaythresholds.(HEPATOLOGY2012;55:1344β1355HepatitisCvirus(HCV)isthemostcommonbloodβborneviralinfectionintheUnitedStates,1affectinganestimated3.6millionU.S.residents.2Themajorityofinfectedindividualsdevelopchronichepatitis;persistentliverinjuryleadstocirrhosisin55 billion per year, 4 with projected HCV-related societal costs for the years 2010-2019 estimated to total $54.2 billion. 5 For the last decade, the standard of care for treating HCV has been the combination of pegylated interferon (Peg-IFN) and ribavirin (RBV), 6 which successfully eradicates virus (sustained virologic response; SVR) in 40%-80% of treated patients