Overwhelming evidence indicates that distinct pathological phenomenon occurs within the gastrointestinal (GI) tract of progressively simian immunodeficiency virus (SIV)-infected Asian macaques and HIV-infected humans compared with other anatomical sites. Massive loss of GI tract lamina propria CD4 T cells, alteration in the profile of lymphocytic cytokine production, changes in the landscape of GI tract antigen-presenting cells, and variations to the structural barrier of the GI tract are hallmarks of progressive HIV/SIV infections. The pathology within the GI tract results in translocation of microbial products from the lumen of the intestine into peripheral circulation. These translocated microbial products directly stimulate the immune system and exacerbate immune activation and, thus, disease progression. Initiation of combination antiretroviral therapy (cART) does not restore completely the immunological abnormalities within the GI tract. This incomplete restoration within the GI tract may contribute to the increased mortality observed within HIV-infected individuals treated for decades with cART. Novel therapeutic interventions aimed at enhancing GI tract anatomy and physiology may improve the prognosis of HIV-infected individuals.