Chronic hepatitis C virus (HCV) infection is associated with mixed cryoglobulinemia (MC) which can be viewed as a low-grade non-malignant B-cell lymphoproliferation. HCV is also associated with overt B-cell lymphomas but the direct causal relationship has remained elusive. The finding that HCV-associated splenic lymphomas with villous lymphocytes (SLVL), a subset of splenic marginal zone lymphomas, is constantly associated with MC and responds to antiviral therapy, and furthermore that the viral load strongly correlates with the tumor burden, lends support to the hypothesis that HCV is associated with antigen-driven B-cell transformation in a mechanism reminiscent of Helicobacter pylori-associated gastric MALT lymphoma. Moreover, the finding that HCV-positive large B-cell lymphomas appear to be transformed from low-grade B-cell lymphomas and that cryoglobulinemia is an independent risk factor for lymphoma in HCV-infected patients add support to this hypothesis. However, HCV-associated antigen-driven lymphomagenesis may not be the sole mechanism by which the virus could induce lymphomas, and a direct transformation of B-cells may be at play in some cases. HCV is among the growing list of pathogens associated with the development of lymphomas. Antiviral therapy should be considered as first-line therapy in low-grade B-cell and possibly large-cell lymphomas associated with HCV, especially in the presence of MC.