As the first step in human immunodeficiency virus (HIV) infection, HIV binds to CD4 molecules on the surface of human T lymphocytes. Expression of CD4 by the cells is remarkably modulated by exogenously added gangliosides, which are normal components of the surface of animal cells. We report here that these physiological molecules also clearly inhibited HIV infection of lymphocytes in vitro in a dose-dependent manner through the selective modulation of CD4 from the cell surface. This raises the possibility of in vivo application of gangliosides as a new strategy for treating acquired immunodeficiency syndrome.