CD55/DAF, one of the regulators of complement activation (RCA), is known to limit excess complement activation on the host cell surface by accelerating the decay of C3 convertase. We have previously reported that hepatitis C virus (HCV) infection or virus core protein expression upregulates CD55 expression. CD55 associates with HCV particles, potentially protecting HCV from lysis in circulation. An increase in CD55 on HCV infected cell surface may inhibit complement mediated cell killing. In this study, we have shown that antibodies against cancer cell surface proteins induce complement dependent cytolysis (CDC) or antibody-dependent cell-mediated cytotoxicity (ADCC) of immortalized human hepatocytes (IHH) in the presence of CD55 blocking antibody. CD55 has a secreted isoform (sCD55) generated by alternative splicing. We have observed that sCD55 is induced in HCV infected or HCV replicon harboring cells, and in liver biopsy samples from chronically HCV infected patients. Conditioned medium from HCV infected hepatoma cells (Huh7.5) or IHH inhibited C3 convertase activity and CDC of sheep blood erythrocytes. Chronically HCV infected patient sera displayed inhibition of C3 convertase activity, further implicating HCV specific impairment of complement function in infected humans. CD55 blocking antibody inhibited erythrocyte lysis by conditioned medium, suggesting CD55/sCD55 has a function for impairing convertase activity. Together, we have shown that HCV infection induces sCD55 expression in HCV infected cell culture conditioned medium, and inhibits C3 convertase activity. This may have implication in modulating complement mediated immune function in the microenvironment and on HCV harboring cells.