The treatment of mixed cryoglobulinemic syndrome must be decided on the basis of the etiopathogenetic cascade that leads from hepatitis C virus infection to multiple immune-system alterations, mainly B-cell proliferation, and lastly to immune complex-mediated small vessel vasculitis. The vasculitic syndrome may be complicated by malignancies, mainly B-cell lymphoma. Accordingly, we can treat mixed cryoglobulinemic syndrome (MCs) at three different levels by means of etiological, pathogenetic, and symptomatic therapies. The use of antivirals, namely peg-interferon-alpha (peg-IFNα) plus ribavirin (RIBA), aims to eradicate the hepatitis C virus (HCV); it represents the etiological treatment of HCV-associated MCs. The anti-CD20 monoclonal antibody rituximab is considered the most useful and safe pathogenetic treatment of MCs. In selected patients with severe, active clinical manifestations, sequential or combined therapy with antivirals and rituximab has been usefully employed (see also Figure 3). CIC, circulating immune complexes; CPX, cyclophosphamide; HLA, human leukocyte antigen; LAC, low antigen-content; LDL, low-density lipoprotein; RF, rheumatoid factor.