Mixed cryoglobulinemia (MC) syndrome is an immune complex-mediated vasculitis characterized by the clinical triad of purpura, weakness, and arthralgias, the morbidity of which is mainly related to kidney and peripheral nervous system dysfunction as well as to the development of a secondary lymphoma (Ferri et al. Autoimmun Rev 7:114-120, 2007, Lidar et al. Ann N Y Acad Sci 1173:649-657, 2009, Trejo et al. Semin Arthritis Rheum 33:19-28, 2003). MC is associated with infectious and systemic disorders, principally autoimmune and lymphoproliferative diseases. Since the 1990s, a striking association (>90%) between MC and hepatitis C virus (HCV) infection has been established (Ferri and Bombardieri 2004; Pascual et al. J Infect Dis 162:569-570, 1990). However, information regarding the etiopathogenesis of HCV-negative MC is scant (Mascia et al. Dig Liver Dis 39:61-64, 2007). We hereby present our findings, as well as previously published data, regarding the presence of antibodies against infectious agents and autoantibodies in patients with MC in an attempt to establish novel associations which may shed light on the etiopathogenesis of this disease.