Hepatitis C virus (HCV) is the most common chronic bloodborne pathogen in the United States. Based on a national survey of households, approximately 1.6 percent of U.S. adults over 20 years of age have antibodies to HCV, indicating prior acute HCV infection. About 78 percent of patients with acute HCV infection develop chronic HCV infection, defined by the presence of persistent viremia. Chronic HCV infection has a variable course, but it is a leading cause of complications from chronic liver disease, including cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Chronic HCV infection is associated with an estimated 15,000 deaths each year in the United States, and it is the most common indication for liver transplantation among American adults, accounting for more than 30 percent of cases. The prevalence of chronic HCV infection is thought to have peaked in 2001 at 3.6 million people, and the yearly incidence has declined from more than 200,000 cases per year in the 1980s to around 16,000 cases in 2009. However, complications related to chronic HCV infection, which frequently occur only after decades of infection, are expected to rise for another 10 to 13 years. The goal of antiviral treatment for chronic HCV infection is to prevent the long-term health complications associated with HCV infection, such as cirrhosis, hepatic decompensation, and liver cancer, but it is extremely difficult to design and carry out clinical trials long and large enough to provide direct evidence related to these outcomes. The sustained virologic response (SVR) rate is the standard marker of successful treatment in clinical trials because an SVR is strongly associated with the long-term absence of viremia. Recent studies have evaluated the association between achieving an SVR and reductions in mortality, liver failure, and cancer. Understanding the comparative benefits and harms of the various antiviral regimens is critical for making informed treatment decisions in patients with chronic HCV infection, particularly given the availability of new treatment options. This review assesses the comparative effectiveness of antiviral treatments in adults with chronic HCV infection who have not received previous antiviral drug treatment. In addition to assessing the comparative effectiveness of different drug regimens, the review evaluates the effects of different medication doses, durations of therapy, and dosing strategies. To help with individualized clinical decisionmaking regarding antiviral therapy for chronic HCV infection, the review also evaluates how comparative effectiveness varies depending on HCV genotype, viral load, and other demographic and clinical characteristics. The following Key Questions are the focus of our report: Key Question 1: a. What is the comparative effectiveness of antiviral treatment in improving health outcomes in patients with HCV infection? b. How does the comparative effectiveness of antiviral treatment for health outcomes vary according to patient subgroup characteristics, including but not limited to HCV genotype, age, race, sex, stage of disease, or genetic markers? Key Question 2: a. What is the comparative effectiveness of antiviral treatments on intermediate outcomes, such as the rate of SVR or histologic changes in the liver? b. How does the comparative effectiveness of antiviral treatment for intermediate outcomes vary according to patient subgroup characteristics, including but not limited to HCV genotype, age, race, sex, stage of disease, or genetic markers? Key Question 3: a. What are the comparative harms associated with antiviral treatments? b. Do these harms differ according to patient subgroup characteristics, including HCV genotype, age, race, sex, stage of disease, or genetic markers? Key Question 4: Have improvements in intermediate outcomes (SVR, histologic changes) been shown to reduce the risk or rates of adverse health outcomes from HCV infection?