Receptors for the Fc portion of immunoglobulins or for the third component of complement (C3) are present on a variety of circulating and fixed tissue cells including granulocytes, monocytes, lymphocytes and glomerular epithelial cells. Cells which lack Fc receptors may express them after infection by herpes simplex virus (HSV)-1, HSV-2, cytomegalovirus or varicella zoster virus. We recently reported that infection by HSV-1 induces both Fc and C3 receptors on human endothelial cells. Glycoprotein E of HSV-1 has been shown to function as an Fc receptor. We now demonstrate that glycoprotein C (gC) of HSV-1 functions as a C3b receptor. This receptor appears following HSV-1, but not HSV-2, infection. Detection of the C3b receptor is blocked by monoclonal antibodies to glycoprotein C (gC) of HSV-1, but not by monoclonal antibodies to other HSV-1 glycoproteins. In addition, the MP mutant of HSV-1, which lacks gC, fails to express a C3b receptor. These results assign a new function of gC of HSV-1 and demonstrate potentially important differences between HSV-1 and HSV-2 glycoproteins.