Hepatitis C virus has a low buoyant density in sucrose, but high-density particles are often observed in hepatitis C virus infection. To investigate the characteristics of circulating hepatitis C virus particles and their association with liver disease progression, we examined sera from two histologically normal hepatitis C virus carriers, 20 chronic hepatitis patients and five acute hepatitis C patients. The supernatants obtained after immunoprecipitation with anti-immunoglobulins antibody were subjected to sucrose equilibrium centrifugation. HCV-RNA positive fractions separated after the treatments were further examined for immunoprecipitation with anti-core hepatitis C virus antibody. We separated hepatitis C virus particle populations according to the density difference on 35% sucrose with centrifugation. The proportions of high and low density particles in hepatitis C virus populations were determined by means of competitive reverse transcription and polymerase chain reaction. Circulating hepatitis C virus particles in chronically infected patients could be separated into two populations: those immunoglobulin-bound with high densities and -unbound with low densities. Patients with severe liver inflammation had high-density hepatitis C virus that did not precipitate with anti-immunoglobulins but with anti-core hepatitis C virus antibodies. Thus, hepatitis C virus particle populations consist of low-density virions and high-density immune complexes and/or nucleocapsids. Among the chronic hepatitis patients, the dominant population shifted from low-density to high-density particles with the progression of liver disease. In acute hepatitis patients, this density shift was observed with alanine aminotransferase normalizations. Therefore, the major hepatitis C virus populations change from virion to immune complex and/or nucleocapsid with the progression of liver disease or inflammation.