Circulating immune complexes (ICs) were isolated by affinity chromatography and sucrose density gradient fractionation during acute and chronic hepatitis C virus (HCV) infection. Immunochemical and biomolecular studies showed that they basically consist of the virus component, IgG with specific anti-HCV activity and IgM bearing 17.109 epitope (IgM 17.109), an antigenic determinant common to rheumatoid factors (RFs) with WA cross-idiotype (XId). An antigen-specific IC assay was used to demonstrate IgG anti-HCV/IgM 17.109 ICs (IgG-IgM ICs) in five out of the five patients with acute and in 8 out of the 10 patients with chronic hepatitis C who mounted an IgG anti-HCV immune response. They were not detected in patients with no IgG anti-HCV response. IgG–IgM ICs appeared in step with IgG anti-HCV seroconversion and remained detectable for a long period irrespective of clinical outcome, in that they were demonstrated over a 4-year follow-up of patients with chronic hepatitis C. Their presence was unrelated to the severity and progression of liver histology. Despite similar serum levels of IgM 17.109 XId, antigen-specific IgG-IgM ICs were not found in acute and chronic hepatitis B or in acute hepatitis A. Thus, these ICs appear to be uniquely associated with HCV infection, supporting the view that IgM 17.109 XId derive from an antigen-driven response strictly related to the involved antigen. Even although they have no apparent effects on the progression of HCV-related liver disease, their presence may help to explain the immunological abnormalities and extrahepatic disorders observed in HCV infection.