Epidemiological data suggest that transmission of human immunodeficiency virus (HIV) occurs primarily by transference of virally infected cells. However, the efficiency of lytic productive infection induced by HIV after transmission of cell‐associated virus vs. free virus is difficult to assess. The present studies compare the extent of depletion of CD4+(helper/inducer) T cells after mixing uninfected cells with either free HIV or irradiated HIV‐infected allogeneic or autologous cells in vitro. Rapid CD4+cellular depletion occurred only in cultures containing allogeneic infected cells or after addition of a nonspecific T cell activation signal to cultures with autologous infected cells. These in vitro observations strongly support the epidemiological implication that interactions between infected and uninfected cells are the most efficient means of transmission and HIV‐induced cytopathology in vivo. They also provide direct support for the concept that immunological stimulation by foreign cells infected with HIV dramatically increases the likelihood of transmission. These in vitro observations suggest a model for the acquisition of HIV in vivo and the role of cellular activation in dissemination of the virus to uninfected cells in an infected individual.—Lewis, D. E.; Yoffe, B.; Bosworth, C. G.; Hollinger, F. B.; Rich, R. R. Human immunodeficiency virus‐induced pathology favored by cellular transmission and activation.FASEB J, 2: 251‐255; 1988.