Epidemiologic and molecular observations have recently suggested that hepatitis C virus (HCV) may be the causative agent of some B-cell non-Hodgkin lymphomas (B-NHL). Epidemiologic data suggest that in Italy about 5% of B-NHL are caused by HCV. Molecular data indicate a close relationship between HCV-associated B-NHL and type II mixed cryoglobulinemia. The latter disorder appears to reflect the benign monoclonal proliferation of B cells expressing a specific cross-reactive idiotype, known as WA, that may recognize an antigen of HCV, perhaps the E2 protein. Genetic abnormalities occurring during this phase of antigen-induced clonal expansion may drive the neoplastic transformation into low- or high-grade lymphoma. The recent demonstration that splenic B cell lymphomas associated with HCV-infection may regress after successful antiviral therapy confirms a role for this virus in B-cell lymphomagenesis.