Hepatitis C virus (HCV) is a major causative agent of chronic hepatitis worldwide. 1-5 Most HCV-infected individuals develop chronic hepatitis progressing eventually to cirrhosis and hepatocellular carcinoma. 6 In the United States, 2.7 million persons are chronically infected with HCV. 7 Drug use and high-risk sexual behavior have been identified as major risk factors for HCV infection. 7 Treatment options for chronic HCV infection are limited. 1,[8][9][10][11] Although the humoral and cellular immune responses induced by HCV have been described in great detail, mechanisms of viral clearance and persistence are still poorly understood. Chronic HCV infection results in the induction of a strong humoral immune response, 1,12 and anti-HCV antibodies can be detected easily using synthetic peptides or recombinant proteins in serologic assays (for review, see Schiff 13 ). Because these antigens are either synthetic peptides or recombinant truncated proteins representing mostly linear epitopes, little information is available regarding anti-HCV antibodies against nonlinear or conformational epitopes and their relevance in the pathogenesis of hepatitis C.HCV is a member of the Flaviviridae family. 4 The virion contains a positive-stranded RNA genome that is translated into a single polyprotein. This polyprotein is processed by host and viral proteases. 5,14 The HCV structural proteins comprise the core protein (C) and the 2 envelope glycoproteins, E1 and E2. We have recently described the synthesis of HCVlike particles (HCV-LPs) in insect cells using a recombinant baculovirus containing the cDNA of the HCV structural protein core, E1, and E2. 15 The insect cell-derived HCV-LPs exhibit similar morphologic and biophysical properties as putative virions isolated from HCV-infected humans. Because HCV-LPs synthesized in insect cells are derived from partial viral genome without the nonstructural genes required for viral replication, they are noninfectious and therefore represent an attractive candidate for HCV vaccine. 16 In contrast to previously described serologic assays, the HCV proteins of HCV-like particles are presumably presented in a native, virion-like conformation, and may therefore interact with anti-HCV antibodies directed against nonlinear or conformational epitopes of HCV envelope proteins that may represent neutralizing epitopes.Abbreviations: HCV, hepatitis C virus; HCV-LP, hepatitis C virus-like particle; E1/E2, envelope glycoproteins 1 and 2; ELISA, enzyme-linked immunosorbent assay; IFN-␣, interferon alfa; ALT, alanine transaminase; PCR, polymerase chain reaction; PBS, phosphate-buffered saline; OD, optical density; SR/NR, sustained responders/nonresponders; Rel, relapsers.From the