The striking association between hepatitis C virus (HCV) infection and the so-called "essential" mixed cryoglobulinemia (MC) has led to the hypothesis that HCV plays a major role in the production of cryoglobulins. Analysis of soluble and cryoprecipitable immune complexes shows that the hepatitis C virion is bound to IgM bearing the WA cross-idiotype (XId). The production of WA XId IgM seems to be the result of chronic stimulation by HCV of a population of WA XId + CD5 + B cells. It is possible that the reactivity of WA XId IgM does not initially include rheumatoid factor (RF) activity, which may be acquired secondarily from mutational events accompanying a probably T-cell independent B cell proliferation. Type II MC is a benign proliferation that progresses to malignancy in a minority of patients. This is consistent with the concept that malignancy progression involves the accumulation of multiple mutations of proto-oncogenes and tumor suppressor genes that are facilitated by chronic antigenic stimulation. The recent demonstration of HCV in hyperplastic reactive lymphoadenopathy and in the neoplastic lymph nodes of patients with MC strengthens the putative role played by HCV in lymphomagenesis. A fuller understanding of the virus-related mechanisms of lymphoproliferation in MC patients would contribute significantly to the development of therapeutic strategies.