We have isolated new MAbs directed against the human fusion regulatory protein 1 (FRP-1; CD98) molecule using human FRP-1-expressing L929 cells as antigens. The biological activities, and in particular the human immunodeficiency virus (HIV)-mediated fusion regulatory activity of seven anti-FRP-1/CD98 MAbs were analysed using the U937/gp160 cell line, which is a CD4+ U937 cell line expressing HIV gp160. Two MAbs induced multinucleated giant cell formation in U937/gp160 cells and the other five MAbs showed no fusion-inducing ability. However, four of these MAbs suppressed multinucleated giant cell formation of U937/gp160 cells induced by the activating anti-FRP-1 MAbs. Interestingly, five of the MAbs induced multinucleated giant cells in peripheral blood monocytes and one MAb showing fusion-inducing ability in U937/gp160 cells suppressed multinucleated giant cell formation of monocytes induced by anti-FRP-1 MAbs. Furthermore, four of the anti-FRP-1 MAbs suppressed cell fusion of Jurkat/gp160 cells, which are Jurkat cells expressing HIV gp160. Thus, FRP-1/CD98 is capable of either activating or inhibiting HIV-mediated cell fusion depending on whether an enhancing or inhibiting antibody is used, indicating that FRP-1/CD98 is a multipotential molecule. Thus, HIV-mediated cell fusion can be regulated by modification of the FRP-1 system. Furthermore, the present study demonstrates that the FRP-1 and FRP-2 systems are interdependent.