Leukocytoclastic vasculitis is the dominant lesion of mixed cryoglobulinemia (MC). The high prevalence of antibodies to hepatitis C virus (HCV) in association with the higher concentration of HCV RNA genomic sequences in the cryoglobulins suggests a close relationship between MC and HCV infection and strongly supports the view that this virus plays a key role in causing vascular damage. Analysis of the composition of immune complexes (ICs) provides evidence that cryoglobulins include virions mostly bound to IgG that is specifically reactive with HCV-related proteins, which in turn are crosslinked by monoclonal IgM with rheumatoid factor (RF) activity, frequently bearing the WA crossidiotype (XId). This structure is similar (if not identical) to that of circulating ICs from HCV-infected patients without cryoglobulins, suggesting that the virus may be directly responsible for the production of WA RF. Evidence for the role of circulating cryoproteins in the pathogenesis of cutaneous and renal vasculitis stems from the demonstration of HCV-related proteins and/or HCV RNA genomic sequences in the vessel wall of patients with MC. Our data indicate that endothelial cells are fully susceptible to infection by and replication of HCV, and support the contention that they serve as sufficient targets for the binding of HCV proteins expressed on the cell surface to serum immunoglobulins. The in situ demonstration of IgM RF WA XId adds further evidence that RF of the WA group participates in the development of vasculitis and probably stabilizes the binding of IgG antibodies. Lymphocytes may be crucial in the infection of endothelial cells by acting as a circulating viral reservoir. After encouraging initial results, controlled trials have defined the substantive efficacy of IFN-alpha in the treatment of MC. A response of IFN can be achieved in more than 50% of patients and includes improvement of cutaneous vasculitis and renal function. This clinical response is accompanied by a reduction in hepatitis C viremia, serum cryoglobulin concentration, and IgM RF synthesis. However, almost 80% of responders eventually have a clinical and biochemical relapse. Additional studies are required to improve the outcome and extension of this therapy, define the best candidates, and indicate the situations in which it is needed.