OBJECTIVES: Hepatitis C virus (HCV) infection is a chronic disease affecting the liver that may lead to cirrhosis and result in costly outcomes including ascites, variceal bleeds, encephalopathy, hepatocellular carcinoma (HCC), and liver transplant. The purpose of this study is to evaluate the overall cost burden of genotype 1 chronic HCV patients treated with current triple therapy regimens (protease inhibitor/peginterferon alfa/ribavirin) or future quadruple therapy regimens (polymerase or NS5A inhibitor/protease inhibitor/peginterferon alfa/ribavirin), and the incremental cost burden of patients identified as having chronic HCV by new screening guidelines. METHODS: A 50-year Markov cohort model was developed to compare current and future HCV treatment regimens. Patients who achieved sustained virologic response (SVR) were considered responders and were assigned a decreased level of progression to HCC, liver transplant, and liver-related mortality. Cost inputs, including pharmacy and medical costs associated with progressive HCV-related liver disease, were derived from published sources and Redbook.  Treatment effectiveness, adherence rates, and transition probabilities for responders and non-responders were derived from published sources. SVR for quadruple therapy was derived from interim phase II trial results. Cost and outcomes were discounted at 3% and tested with a one-way sensitivity analysis. RESULTS: The discounted cost to treat a patient with triple therapy is US$150,790, including pharmacy costs and hepatic sequelae. Assuming treatment at time of drug approval, the corresponding discounted cost for quadruple therapy is projected at US$205,045 per patient. Based on proposed screening guidelines, approximately 150,000 additional chronic HCV patients will be both diagnosed and treated.  The incremental discounted cost of treating these additional patients with quadruple therapy is projected to be $28.5 billion and is due in part to increased patient lifespan. CONCLUSIONS: New screening guidelines and therapeutic advances are projected to improve patient utilization of more effective treatments and result in an increased level of healthcare spending.