Recombinant soluble CD4 (rCD4) has been shown to be an effective inhibitor of human immunodeficiency virus type 1 (HIV-1) and HIV-2 infection of lymphoid cells in vitro. In this report, we characterized the effects of rCD4, the V1V2 fragment of CD4, and the immunoadhesin CD4-immunoglobulin G on syncytium formation between lymphoid cells infected by HIV-1 or HIV-2 and uninfected cells. All three molecules blocked HIV-1-mediated syncytium formation, but only CD4-immunoglobulin G blocked HIV-2-mediated syncytium formation. rCD4 and the V1V2 fragment of CD4 enhanced HIV-2-mediated syncytium formation. These results suggest that the process of cell fusion is significantly different between HIV-1- and HIV-2-infected cells.