Herpes simplex virus type 1-infected cells bind C3b and iC3b, but not C3d, at the cell surface. Herpes simplex virus type 2 (HSV-2)-infected cells bind none of these C3 fragments. A transfection assay was used to demonstrate that binding of iC3b was to gC1. Although iC3b did not bind to HSV-2-infected cells, it did bind to mammalian cells transfected with the gC2 gene. Using linker insertion mutants, three domains on gC2 that are important for binding iC3b were mapped; these regions were similar to previously defined regions involved in binding C3b. These results suggest that some of the functions served by gC may be similar to those of CR3, the mammalian receptor for iC3b.