Observations from our laboratory support the theory that HIV-infected monocyte-macrophages present in genital tract secretions have an important role in sexual transmission of HIV. Light and electron microscopy were used to study the behavior of HIV-infected, primary human monocytes. These cells progress on surfaces, putting forward a leading pseudopod from which they secrete HIV. When added to cultures of CD4-, cervix-derived epithelial cells, monocytes advanced between epithelial cells while secreting virus anteriorly. Epithelial cells subsequently become productively infected. Infection of epithelia could be blocked by sera from HIV-seropositive individuals. These findings support the supposition that transmission of HIV may occur via cell-mediated infection of intact epithelia. The observations also hint at the possibility that HIV-infected monocyte-macrophages in semen or cervical-vaginal secretions could cross intact epithelia by passing between epithelial cells. To test this hypothesis supravital-stained mouse macrophages were inoculated into the vaginas of mice. Four hours later numerous stained cells were observed in the connective tissue beneath the vaginal epithelium and in the iliac lymph nodes. We speculate that direct infection of epithelial cells and/or cell trafficking across epithelia may be involved in sexual transmission of HIV.