Purpose: Current screening guidelines for hepatitis C virus (HCV) infection use risk factors to identify people who should be tested for HCV. The success of these AASLD guidelines in detecting infected patients depends on several factors including: physicians' knowledge about risk factors, access to accurate patient information, and patient-physician interaction time to investigate the existence of the factors. Despite risk-based screening, approximately 75% of patients with HCV remain undiagnosed. In this study, we examined a onetime, birth-year-based screening strategy, and compared its performance with that of risk-based screening. Methods: Risk factors based on current AASLD guidelines were applied to NHANES data to estimate the predictive performance of the screening strategy under ideal conditions (i.e. testing for anti-HCV antibody for any person who has any of the risk factors). The birth cohort screening would test all persons born between 1946 and 1964 as this cohort accounts for roughly two-thirds of the HCV-infected population. Results: Using risk-based guidelines under ideal circumstances, where everybody has access to health care and patient history and birth year are known, 24.7% of the US population over 20 years old could be screened; of these, 6.8% would be diagnosed with HCV. Of the overall projected HCV population, 82.4% would be correctly identified as such. Alternatively, the targeted birth cohort screening strategy could screen 44.8% of the US population over the age of 20 years; of these, 3.5% would be diagnosed with HCV. Of the overall projected HCV population, 76.1% would be correctly identified as infected with HCV. Conclusion: Targeted birth-year-based screening had a similar theoretical performance to risk-based screening in predicting the presence of HCV infection (76% vs. 82%, respectively). However, despite the theoretical predictive power of risk-based screening (82%), it is currently estimated that 75% of chronically HCV-infected patients are undiagnosed, which may reflect the limitations on the real-world effectiveness of risk-based screening. As patient age is typically known by physicians, targeted birth-year-based screening may have the potential to eliminate some key risk-based screening dependencies. Therefore, real world implementation of birth-year screening would be easier compared with risk-based screening and could potentially lead to outcomes closer to theoretical results. A birth-year screening strategy could result in screening more people compared with risk-based screening; further studies are needed to assess the economic impact of this strategy.