Mixed cryoglobulinemia (MC) type II is a disorder characterized by circulating cold-precipitable immune complexes composed of polyclonal immunoglobulin IgG and monoclonal IgM rheumatoid factor (RF). The systemic vasculitis which characterizes the disease is caused by the deposition of immune complexes on the walls of small vessels, and by the subsequent activation of the complement cascade. MC may be asymptomatic or lead to clinical manifestations characterized by a typical triad--purpura, arthralgia, and weakness--and in some cases by a more serious vasculitis with neurologic and renal involvement. In the vast majority (more than 90%) of patients, MC is associated with hepatitis C virus (HCV) infection, which is considered the triggering factor of the disease. The association between cryoglobulinemia and HCV infection, and the possible evolution to B-cell lymphomas usually after long-term follow-up, suggest the role of HCV infection both in the pathogenesis of MC and in lymphomagenesis. In fact, the virus chronically stimulates the polyclonal proliferation of B cells from which a monoclonal population may emerge. This paper also reviews the treatment strategies for MC syndrome, emphasizing the issue of the eradication of HCV, and the clinical and biological activity of rituximab for selective B-cell control.