Mixed cryoglobulinemia occurs in about half of all patients with chronic hepatitis C. Mixed cryoglobulinemia results from a lymphoproliferative disorder caused by polyclonal lymphocyte B proliferation (type III) or expansion of a B-cell clone producing monoclonal Ig with anti-immunoglobulin activity (type II). Among the different viral infections studied to date (hepatitis A or B, cytomegalovirus, Epstein-Barr or herpes simplex virus) none except hepatitis C has been formally linked to cryoglobulinemia. The mechanisms involved with the hepatitis C virus and persistant cryoglobulinemia are unknown. Several studies have shown that the hepatitis C virus plays a distinct role in the pathogenesis of cryoglobulinemia. The high content of anti-HVC antibodies and viral RNA in the cryoprecipitates suggests that entire viral particles or encapsidized viral RNA may be involved. Viral variability over time and within the same individual might be responsible for repeated antigenic stimulation of the immune system leading to proliferation or expansion of the B-cell clone.