In this systematic review, we focus on whether it is useful to test for anti-hepatitis C virus (anti-HCV) antibody (Ab) in asymptomatic adults who have no history of liver disease or known liver function test abnormalities. The review is intended for use by the US Preventive Services Task Force (USPTF), which will make recommendations regarding screening in the general adult population or high-risk subpopulations. HCV is acquired primarily by large or repeated percutaneous exposures to blood. In approximately 1/3 of patients, acute HCV infection causes symptomatic illness (primarily jaundice, nausea, right upper quadrant pain, or fatigue) after a mean incubation period of 7 weeks. In other patients, acute HCV infection is anicteric and not associated with symptoms or transaminase elevations. HCV viremia is detectable in the blood within 2 weeks of acute infection. The natural course of chronic HCV infection varies widely. A proportion of patients with chronic HCV infection have only mild liver disease even after decades of infection or never develop histologic evidence of liver disease. In other patients, inflammation and fibrosis of the liver may progress to cirrhosis, which can lead to end stage liver disease (ESLD) or hepatocellular carcinoma (HCC). Once cirrhosis develops, patients have a much higher risk of death, and some may benefit from liver transplantation. The strongest predictors of a progressive course of chronic HCV infection appear to be older age at acquisition, co-morbid medical conditions (such as heavy alcohol use, HIV, and other chronic liver disease), and duration of infection. The mode of acquisition, viral load, transaminase level, and viral genotype have not been established as consistent predictors of disease progression, though some cross-sectional and longitudinal studies have found associations. Estimating the proportion of patients in the general population with HCV infection who will progress to cirrhosis has been difficult because the time of acquisition is rarely recognized, particularly in asymptomatic patients, and a long duration (decades) is required to track patients to important endpoints. Factors affecting the rate of cirrhosis in a particular population include the prevalence of co-morbid conditions, the age at acquisition, the proportion receiving treatment, and whether the population was referred or community-based. Most data on the natural history of HCV infection has been in referral populations, but community-based cohort studies appear to be more representative of the general population. Questions addressed include: 1: Does screening for hepatitis C reduce the risk or rate of harm and premature death and disability? 2: Can clinical or demographic characteristics identify a subgroup of asymptomatic patients at higher risk for HCV infection? 3: What are the test characteristics of HCV antibody testing? 4: What is the false-positive rate and what are the harms associated with screening for hepatitis C virus? 5a: What are the test characteristics off the work-up for treatable disease? 5b: In patients found to be positive for hepatitis C antibody, what proportion of patients would qualify for antiviral treatment? 6: What are the harms associated with the work-up for active HCV disease? 7a: How well does antiviral treatment reduce the rate of viremia, improve transaminase levels, and improve histology? 7b: How well does antiviral treatment improve health outcomes in asymptomatic patients with hepatitis C? 7c: How well do counseling and immunizations in asymptomatic patients with hepatitis C improve clinical outcomes or prevent spread of disease? 8: What are the harms (including intolerance to treatment) associated with antiviral treatment? 9: Have improvements in intermediate outcomes (liver function tests, viral remission, histologic changes) been shown to reduce the risk or rate of harm from hepatitis C?