Cryoglobulinemia refers to the presence in serum of immunoglobulins that precipitate at a cold temperature. Type I cryoglobulins are single monoclonal immunoglobulins usually associated with haematological disorders. Types II and III are mixed cryoglobulins, composed of monoclonal or polyclonal IgM respectively, having rheumatoid factor activity that bind to polyclonal immunoglobulins. Mixed cryoglobulinemia (MC) syndrome is a consequence of immune-complex mediated vasculitis and is characterized by a typical clinical triad: purpura, weakness, arthralgias; many organs particularly kidney and peripheral nervous system may be involved. MC may be associated with infectious and systemic disorders and since 1990 studies have demonstrated that hepatitis C virus (HCV) may be considered the principal trigger of the disease. The relation between MC and HCV infection shows new insights in the interpretation of the link between viral infection, autoimmune phenomena and lymphoproliferative disorders evolution. In fact, the virus chronically stimulates B-cell polyclonal proliferation from which a monoclonal population may emerge. In symptomatic patients with HCV related MC therapeutic strategy should include an attempt at viral eradication. Antiviral therapy may also be effective in determining the regression of B-cell lymphoproliferative disorder. Rituximab could represent a safe and effective alternative to standard immunosuppression and exerts selective B-cell control.