Hepatitis C virus (HCV) is a single-stranded, positive-sense RNA virus of the family Flaviviridae. HCV is the most common chronic bloodborne pathogen in the U.S. The prevalence of anti-HCV antibody in the U.S. is estimated at 1.6 %. Approximately 78 % of those who test positive for anti-HCV antibody have the HCV detectable in the blood (viremia), indicating chronic infection; those with anti-HCV antibody but no viremia are considered to have cleared the infection. The prevalence of chronic HCV infection is thought to have peaked in 2001 at 3.6 million people. The yearly incidence of HCV infection averaged more than 200,000 cases per year in the 1980s, but by 2001 had declined to around 25,000 cases per year. The Centers for Disease Control and Prevention (CDC) estimated 16,000 new cases of HCV infection in 2009. HCV infection is a leading cause of complications from chronic liver disease and was associated with an estimated 15,000 deaths in the U.S. in 2007. One study estimated that the total number of patients with cirrhosis will peak at 1.0 million in 2020, though rates of hepatic decompensation and liver cancer are expected to continue to rise for another 10 to 13 years given the long lag time between infection and development of cirrhosis and other complications. Screening for HCV infection in asymptomatic adults who have no history of liver disease or known liver enzyme abnormalities may identify infected patients at earlier stages of disease, before they develop serious or irreversible liver damage. A high proportion of people with chronic HCV infection are thought to be unaware of their status. The purpose of this report is to review the evidence screening for chronic HCV infection in asymptomatic adults without known liver enzyme abnormalities. The Agency for Healthcare Research and Quality, which commissioned this review, also commissioned a separate but complementary review on effectiveness of antiviral treatments. These reviews will be used by the USPSTF to update its recommendations on HCV screening. This review focuses on research gaps identified in the 2004 USPSTF review and new studies published since that review. The following Key Questions are the focus of our report: Key Question 1: a. Does screening for HCV infection in nonpregnant adults without known abnormal liver enzymes reduce mortality and morbidity due to HCV infection, affect quality of life, or reduce incidence of HCV infection? b. Does screening for HCV infection during pregnancy reduce vertical transmission of HCV or improve mortality or morbidity for the mother or child? Key Question 2: a. What is the effectiveness of different risk- or prevalence-based methods for screening for HCV infection on clinical outcomes? b. What is the sensitivity and number needed to screen to identify one case of HCV infection of different risk- or prevalence-based methods for screening for HCV infection? Key Question 3: What are the harms associated with screening for HCV infection, including adverse effects such as anxiety, labeling, and impact on relationships? Key Question 4: a. What is the comparative effectiveness and comparative diagnostic accuracy of various tests and strategies for the workup to guide treatment decisions in patients who are HCV positive? b. What proportion of patients with screen-detected HCV infection receives treatment? Key Question 5: What are the harms associated with the workup for guiding treatment decisions? Key Question 6: a. How effective is counseling or immunizations of patients with HCV infection at improving health outcomes or reducing the spread of HCV? b. Does becoming aware of positive HCV infection status decrease high-risk behaviors? c. How effective is counseling or immunization of patients with HCV infection at improving intermediate outcomes, including change in high-risk behaviors? Key Question 7: Do any interventions decrease or increase the vertical transmission of HCV during delivery or in the perinatal period?