Hepatitis C virus (HCV) RNA detection, viral load quantification, and HCV genotyping are widely used in clinical practice. Recently, the availability of an anticore antigen (Ag) monoclonal antibody allowed development of an enzyme-linked immunosorbent assay (ELISA) detecting and quantifying total HCV core Ag in peripheral blood of HCV-infected patients. The aims of the present study were to investigate the biologic significance of this new marker in HCV infection, to establish the intrinsic performance of the current assay, and to determine its potential utility in the management of HCV-infected patients. A panel of infected sera calibrated to the World Health Organization International Standard and 657 serum samples from infected patients receiving antiviral treatment were studied. We showed that total HCV core Ag quantification is an accurate, precise, and specific indirect marker of HCV replication. We estimated that 1 pg/mL of total HCV core Ag is equivalent to approximately 8,000 HCV RNA international units (IU)/mL, although minor between-patient differences may exist. In conclusion, total HCV core Ag quantification can be used in the various indications of viral load monitoring, including the evaluation of baseline viral load before therapy, the assessment of the virologic response to antiviral treatment, and the study of early viral kinetics during therapy. Nevertheless, the total HCV core Ag assay cannot be used as a marker of viral replication for HCV RNA values below 20,000 IU/mL, limiting its use in the monitoring of late events during and after antiviral treatment. (HEPATOLOGY 2002;36:211-218.) H epatitis C virus (HCV) is a single-strand RNA virus belonging to the Flaviviridae family. Its genome is contained in an icosahedral capsid (or core), itself contained within the viral envelope. The capsid is formed by polymerization of the HCV core protein, a structural viral protein encoded by the 5Ј end of the HCV open reading frame. 1 After translation, host signal peptidases cleave the HCV core protein from the precursor polyprotein and remove the signal peptide located at its C-terminus. 1 The mature HCV core protein is a 21-kd phosphoprotein made of the 191 first amino acids of the polyprotein. In the cytoplasm of infected cells, it is located in close vicinity to the perinuclear membranes and the endoplasmic reticulum, where it polymerizes in the presence of genomic RNA to form viral capsids. 1 The HCV core protein is antigenic, interacts with numerous cellular proteins, induces specific cellular and humoral responses, 2,3 and through various pathways could play an important role in the pathogenesis of HCV infection. 4 Virologic diagnosis and monitoring of HCV infection are based on the use of serologic assays detecting specific anti-HCV antibodies (including anticore antibodies), and assays that can detect, quantify or characterize the components of HCV viral particles. 5 In past years, clinical hepatitis C studies have for the most part used molecular biology-based HCV RNA techniques. Indeed, HCV RN...