Mixed cryoglobulinemia (MC) is a systemic vasculitis of small to medium-sized vessels due to the vascular deposition of circulating immune-complexes (CIC) and complement. A leukocytoclastic vasculitis is the histologic hallmark of cutaneous manifestations of the disease, while a clonal B lymphocyte expansion in blood, bone marrow, liver, and spleen represents the underlying pathologic alteration responsible for the production of cryo-CIC and non-cryo CIC with rheumatoid factor activity. A causative role of hepatitis C virus (HCV) infection has been demonstrated in the large majority of MC patients. Hepatitis C virus is both a hepatotropic and a lymphotropic virus; due to this latter biological peculiarity, HCV may trigger a constellation of autoimmune-lymphoproliferative disorders. Besides MC, other important HCV-related diseases are porphyria cutanea tarda, autoimmune hepatitis, membranoproliferative glomerulonephritis, and B cell neoplasias. Hepatitis C virus-related MC represents a link between autoimmune and lymphoproliferative disorders; moreover, MC is an important model to study the complex relation between infections and immune system alterations in humans. During the last years many other autoimmune manifestations have been correlated with HCV infection; namely, sicca syndrome, chronic polyarthritis, polydermatomyositis, fibromyalgia, autoimmune thyroiditis, lung fibrosis, and diabetes mellitus. It is often difficult to verify whether the above associations are coincidental or a pathogenetic link actually exists. At least for particular patients' subsets and in some geographic areas, a causative role of HCV seems to be likely. The geographically heterogeneous distribution of HCV-related autoimmune diseases suggests the contribution of important environmental and genetic factors in the pathogenesis of such conditions. In clinical practice, patients with recent-onset, atypical rheumatic and autoimmune disorders should be carefully investigated for possible HCV infection; this is particularly advisable for correct diagnosis and adequate therapeutic strategy.