The intestinal (in particular rectal) mucosa is an important portal of entry of human immunodeficiency virus (HIV) in homosexual men, who represent the vast majority of HIV-infected patients in Europe and North America. There are several possibilities for HIV to reach the CD4+ T cells, macrophages, and follicular dendritic cells in the intestinal mucosa. HIV may be transported through M cells directly to mucosal lymphoid follicles. Alternatively, HIV may infect enterocytes via Fc-receptor by antibody-bound HIV or via a CD4 independent receptor. By successive budding on the basal side of enterocytes, HIV may be released into the lamina propria. Furthermore, in patients not infected by the intestinal route, HIV may also rapidly enter the intestinal mucosa by other mechanisms: intestinal T-lymphocytes are mainly activated memory T cells reentering the mucosal surfaces after circulating through the peripheral blood. In the periphery they may have been preferentially infected by HIV. Accumulation of infected T cells could thus occur in the intestinal mucosa. The special phenotypical and functional characteristics of intestinal T lymphocytes may affect the replication and cytopathicity of HIV, resulting in an accelerated loss of CD4 positive T cells in the lamina propria. CD4 T cells play a critical role in antigen-dependent B cell differentiation, thus the pronounced CD4 T cell depletion in the intestinal mucosa may be responsible for the observed decrease of IgA plasma cells and a reduced secretion of IgA2. Depletion and functional impairment of activated mucosal lamina propria lymphocytes by HIV infection could explain the break-down of the mucosal immune barrier leading to secondary opportunistic or nonopportunistic infections and secondary malignancies. In addition, because of the interrelation between the mucosal immune system and the epithelium these changes might be responsible for the partial small intestinal mucosal atrophy and maturational defects in enterocytes observed in HIV-infected patients. To be effective, a future prophylactic vaccine against HIV has to be able to induce not only systemic but also a local mucosal cellular and humoral protective immune response.