Human immunodeficiency virus (HIV) infects cells of the monocyte/macrophage lineage in addition to lymphocytes, and infection of these cells may be responsible for viral persistence and dissemination, encephalopathy of the acquired immunodeficiency syndrome and other sequelae of HIV infection. We have developed an in vitro model utilizing peripheral-blood monocyte-derived macrophages to study HIV-1 infection of macrophages. HIV-1 isolates vary greatly in their ability to infect and replicate in macrophages, from highly restricted to highly productive infection. Productively infected macrophages undergo syncytium formation but remain viable in culture and support sustained levels of virus production for prolonged periods. Transformed monocytoid and lymphoid cell lines, however, show very different patterns of permissiveness for HIV-1 strains and do not reflect their corresponding primary cell types in studies of host cell tropism. Studies on viral entry show that the CD4 molecule, known to be the HIV receptor on lymphoid cells, is expressed at low levels on the surface of macrophages as well, where it functions as the receptor for viral entry. Therefore, differential host cell tropism does not result from the use of an alternative macrophage-specific receptor instead of CD4.