HSV-1 glycoprotein C binds complement component C3b and inhibits the interaction of C5 and properdin (P) with C3b, blocking activation of both the classical and alternative complement pathways. HSV-1 gC prevents complement-mediated neutralization of cell-free virus, inhibits complement-mediated lysis of infected cells, and contributes to virulence in vivo, as viruses deficient in binding C3b or blocking C5 and P from interacting with C3b are more attenuated than wild-type virus in a murine flank model of infection.