The pathogenesis of human immunodeficiency virus has long been thought to center on a gradual depletion of CD4⁺ T cells, with an average of 100 cells lost per microliter of blood per year. However, studies of macaques infected with simian immunodeficiency virus and humans infected with human immunodeficiency virus have shown that the infection rapidly kills most CD4⁺ T cells at mucosal surfaces. Although most CD4⁺ T cells reside at these sites, the magnitude of this assault on the immune system is not reflected in the peripheral blood. Here we consider models of human immunodeficiency virus disease pathogenesis given those findings and propose a hypothesis to account for particular aspects of the disease during the chronic phase of infection that can be directly attributed to early depletion of mucosal CD4⁺ T cells.