SUMMARY: Performance characteristics of rapid assays for hepatitis C virus antibody were evaluated in 4 National HIV Behavioral Surveillance System injection drug use sites. The highest assay-specific sensitivities achieved for the Chembio, MedMira and OraSure tests were 94.0%, 78.9%, and 97.4%, respectively; the highest specificities were 97.7%, 83.3%, and 100%, respectively. BACKGROUND: The Centers for Disease Control and Prevention (CDC) estimates that 4.1 million Americans have been infected with hepatitis C virus (HCV) and 75%-80% of them are living with chronic HCV infection, many unaware of their infection. Persons who inject drugs (PWID) account for 57.5% of all persons with HCV antibody (anti-HCV) in the United States. Currently no point-of-care tests for HCV infection are approved for use in the United States. METHODS: Surveys and testing for human immunodeficiency virus (HIV) and anti-HCV were conducted among persons who reported injection drug use in the past 12 months as part of the National HIV Behavioral Surveillance System in 2009. The sensitivity and specificity of point-of-care tests (finger-stick and 2 oral fluid rapid assays) from 3 manufacturers (Chembio, MedMira, and OraSure) were evaluated in field settings in 4 US cities. RESULTS: Sensitivity (78.9%-97.4%) and specificity (80.0%-100.0%) were variable across assays and sites. The highest assay-specific sensitivities achieved for the Chembio, MedMira, and OraSure tests were 94.0%, 78.9% and 97.4%, respectively; the highest specificities were 97.7%, 83.3%, and 100%, respectively. In multivariate analysis, false-negative anti-HCV results were associated with HIV positivity for the Chembio oral assay (adjusted odds ratio, 8.4-9.1; P < .01) in 1 site (New York City). CONCLUSIONS: Sensitive rapid anti-HCV assays are appropriate and feasible for high-prevalence, high-risk populations such as PWID, who can be reached through social service settings such as syringe exchange programs and methadone maintenance treatment programs.