Mononuclear phagocytes which express the HIV entry receptor CD4 have been implicated as possible sites of virus replication in brain, but there is still considerable uncertainty as to which cells in the CNS express CD4 Ag. Although it is not susceptible to HIV infection the rat provides a model to define expression of the CD4 Ag on MO in brain. We report that the CD4 epitopes W3/25 and OX35 are found only on monocytes, MO, microglia, and occasional lymphocytes and not on neurons, other glia, or endothelium. CD4 Ag levels are modulated during microglial differentiation, after reactivation after local inflammation, and within the intact blood brain barrier. MO and microglia also express other potential plasma membrane binding and entry sites for HIV viz Fc and complement receptors that are regulated independently of CD4.