OBJECTIVES: The seroprevalence of hepatitis C virus (HCV) is 16-41% in United States (US) prisons, yet no standard protocols exist for HCV screening. The objective of our study was to evaluate the cost-effectiveness HCV screening in prisons and HCV prevention in society by interventions in prisons. METHODS: We developed an agent-based simulation model that simulated the transmission and progression of HCV disease in US population in prisons and society. Injection drug use was the main route of HCV transmission. Chronic stages of HCV were modeled as Markov states. We used US Department of Justice data to simulate movement of people between prisons and society. We evaluated two screening scenarios: no screening, and 1-time screening of all existing inmates followed by screening (and treatment) of any incoming inmate for 5 years (5YR screening). We projected the total cost, quality-adjusted life years (QALYs), cumulative incidence of cirrhosis, decompensated cirrhosis (DC), hepatocellular carcinoma (HCC), and liver-related deaths (LRD). We also projected the number of new HCV infections in society due to HCV-infected people released from prisons. RESULTS: The total costs under no and 5YR screening were $6.9 million and $8.3 million per 10,000 people, respectively for 30-year simulation. The corresponding QALYs were 190,428 and 190,462, respectively. The incremental cost-effectiveness ratio of 5YR screening was $43,000 per QALY. In comparison with no screening, 5YR screening can avoid 136,000 new HCV infections in the next 30 years, where