Entry of HIV‐1 into host cells is generally mediated by the cell surface CD4 receptor after specific interaction with the viral envelope glycoprotein gp120. Infection by HIV‐1 commonly leads to the disappearance of CD4 from the plasma membrane, a phenomenon referred to as receptor down‐modulation. This, in turn, renders cells refractory to subsequent infection by the same or other viruses that use the CD4 receptor for entry, creating a state of superinfection immunity. CD4 down‐modulation is a complex process involving a variety of viral gene products, the effects of which may be manifest at different stages within the viral replication cycle. CD4 disappearance from the cell surface occurs in each of the CD4 + lymphocytes, T‐cell lines, monocytic cell lines, and monocyte‐derived macrophages. Internalization of CD4 can occur after binding of either gp120 alone or gp120 antigen‐antibody complexes, and may also be mediated by the HIV‐1 Nef gene. Other factors that cause cell surface CD4 depletion include reductions in CD4 transcript levels, impaired translation of CD4 mRNA, formation of CD4‐gp160 intracellular complexes, and degradation of CD4 mediated by the HIV‐1 Vpu gene.— Geleziunas, R., Bour, S., Wainberg, M. A. Cell surface down‐modulation of CD4 after infection by HIV‐1. FASEB J. 8: 593‐600; 1994.