Chronic hepatitis C virus (HCV) infection is the most common cause of chronic liver disease in the United States, affecting more than 2.7 million people.1 Most cases of acute HCV result in chronic infection despite the appearance of antibodies to both structural and nonstructural HCV antigens. Hepatitis C replicates rapidly, at an estimated 1012 virions per day,2 and has a high mutation rate of approximately 10 3 nucleotide substitutions per genome site per year.3 The host humoral immune response contributes to the generation of viral diversity. Although HCV infection frequently becomes chronic, neutralizing antibodies to viral epitopes have been identified. Neutralizing antibodies interfere with viral binding to cellular receptors and entry into hepatocytes through antibody coating of the virus or by inducing conformational changes in viral structural proteins. Neutralizing antibodies differ from binding antibodies by their ability to prevent viral infectivity. The lack of a cell-culture system supporting efficient HCV replication and particle assembly has made it difficult to characterize the envelope proteins present on the virion and to elucidate the process of viral binding and entry into hepatocytes.4 Two structural glycoproteins that form the viral envelope, named E1 and E2, are a target for the host immune response and also represent the putative viral attachment proteins. A recent study that used a cell fusion assay to examine the initial steps of HCV infection showed that the presence of both chimeric E1 and E2 proteins were necessary for cell fusion and that low-pH treatment enhanced the fusion activity of the HCV envelope proteins.5 The experimental findings suggested that HCV enters target cells through an endosomal pathway and that a low-pH– dependent conformational change of the E1 and/or E2 proteins occurs in the endosome that leads to membrane fusion and nucleocapsid entry into the cytoplasm. The N-terminus of the E2 protein contains a specific region approximately 27–31 amino acids in length, termed hypervariable region (HVR) 1, that appears to lack structural constraints and allows extensive amino acid variation. This region likely forms part of the E2 protein located outside the HCV envelope, where it is a prime target of neutralizing antibodies.6 Variability in the amino acid sequence of HVR1 among different isolates results from humoral immune pressure leading to the selection of escape mutants.6,7 Studies showing conservation of HVR1 in an agammaglobulinemic patient,8 a reduced rate of HVR1 variability in patients with common variable immunodeficiency compared to patients with normal immune responses,9 and a marked decrease in nucleotide diversity of HVR1 in human immunodeficiency virus–infected patients with CD4 counts 50/ L10 support the hypothesis that the immune response is important in driving generation of viral diversity. The development of mutations in HVR1 may contribute to viral persistence. Other factors that may play a role in persistent infection include the relatively low immune reactivity of HCV proteins, the high specificity of antibodies to HVR1 that do not cross-neutralize emerging quasispecies (multiple isolates in the same individual), and an inadequate cytotoxic T-lymphocyte response to viral epitopes.11–14 This review analyzes the characteristics of naturally occurring and vaccine-induced hepatitis C antibodies, their role in the course of infection, and possible clinical uses of these antibodies.