Hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis delta virus (HDV) share same transmission routes, thus dual or triple infection may occur and even persist in the same patients. A significant amount of literature has accumulated since the advent of HCV assays. It is pertinent to review and evaluate the clinical and virological significance of HCV in multiple hepatotropic viral infection. The reported series on seroprevalence of HCV indicate that HCV is found in more than 10% of HBV- or HDV-infected patients worldwide. Of the patients with dual or triple infection involving HCV, those having coreplication of viruses tend to have severe and progressive liver disease that is resistant to interferon therapy, in contrast with patients having a single virus infection. Paradoxically, dual or triple hepatitis virus infections are associated with viral interference. In particular, HCV exerts a suppressive effect on HBV and HDV and may enhance seroclearance of HBV antigens or even usurp the role of preexisting virus as the agent for continuing hepatitis. Although HBV and HDV may also suppress HCV, it appears to be less effective. These findings clearly suggest the necessity of monitoring patients with HBV or HDV infections. In view of complex dynamism of viral interaction in multiple hepatotropic virus infection, the importance of HCV assay in the clinical studies can not be overemphasized. The basic mechanisms that regulate the viral interactions, in particular the impact of HCV in dual or triple virus infections, remain to be investigated.