Mixed cryoglobulinemia (MC) is a Iymphoproliferative disorder observed in -lO to 15% of hepatitis C virus (HCV)-infected patients. Circulating, nonenveloped HCV core protein, which has been detected in cryoprecipitable immune complexes, interacts with immunocytes through the receptor for the globular domain of C1q protein (gClq-R). In this study, we have evaluated circulating gClq-R levels in chronically HCV-infected patients, with and without Me. These levels were signi6cantly higher in MC patients than in those without MC and in healthy controls and paralleled specifìc mRNA expres ion in PBL. Soluble gC1q-R circulates as a complexed form containing both Clq and HCV core proteins, Higher serum gC1q-R levels negatively correlated with circulating concentrations or the C4d fragment. The presence or sequestered C4d in the vascular bed of skin biopsies from MC patients was indicative of in situ complement activation. In vitro tudies showed that release or soluble gClq-R is regulated by HCV core-mediated inhibition of celi proliferation. Our results indicate that up-regulation or gC1q-R expression is a distinctive feature of MC, and that dysregulated shedding of Cl q-R molecules contributes lo vascular cryoglobulin-induced damage via the c1assic complement-mediated pathway. The Iournal oJ Immunology, 2009, 183: 6013