Several viruses are involved in the development of systemic vasculitides. Hepatitis C virus (HCV) has been shown to be closely related to mixed cryoglobulinaemia, an immune complex-mediated vasculitis. HCV particles and non-enveloped nucleocapsid protein participate in the formation of immune complexes. Once formed, immune complexes precipitate in many organs, including the skin, kidneys, and peripheral nerve fibres. Viral proteins confer peculiar physical and chemical properties on cryoimmunoglobulins. Since expansion of rheumatoid factor-synthesising B cells is the biological hallmark of mixed cryoglobulinaemia, it may be that the combination of rheumatoid factor activity and cryoprecipitability is responsible for the vasculitis. B-cell clonal expansion occurs primarily in the liver and correlates with a high intrahepatic viral load, pointing to a major role for HCV in the emergence and maintenance of B-cell clonalities. Recognition of HCV as an aetiological factor in most cryoglobulinaemic vasculitides has dramatically changed the approach to their treatment. Emphasis, in fact, is now placed on abatement of the viral load and deletion of B-cell clonalities.