The therapeutic strategy for mixed cryoglobulinemic syndrome may be modulated according to the clinical status of individual patients. We can consider at least four clinical conditions. Mixed cryoglobulinemic syndrome (MCs) may be completely asymptomatic or it may sporadically show very mild manifestations, such as fleeting purpuric lesions on the legs; in these cases monitoring may be sufficient, while an attempt at HCV eradication may be considered. On the opposite side are patients with severe, rapidly progressive cryoglobulinemic vasculitis that must be treated with aggressive combined treatment similar to that used for other systemic vasculitides. Sequential or combined treatment with antivirals and rituximab may be usefully employed in selected patients with severe manifestations. The order of sequential treatment may be decided on the basis of prevalent organ manifestation(s), even if the combined therapy seems to be comparable for efficacy and safety. CPX, cyclophosphamide; CS, corticosteroid; LAC, low antigen-content; peg-IFN, peg-interferon; RIBA, ribavirin; RTX, rituximab.