Evidence is increasing that HIV/SIV-induced changes in the highly differentiated gut-associated immune system play a central role in the pathogenesis of gastrointestinal manifestations in HIV/SIV infection. It has been shown in both humans infected with HIV and in nonhuman primates infected with SIV that a rapid, very early, and more pronounced loss of CD4+ T-cells occurs in the mucosa in comparison to the peripheral blood. The loss of this important regulatory T-cell subset might explain mucosal immunodeficiency with the consequence of opportunistic mucosal infections. In addition, there is evidence that small intestinal damage occurs independently of secondary infections (HIV/SIV enteropathy). In late-stage human disease, HIV enteropathy is characterized by villous atrophy with hyporegeneration and dysmaturation of intestinal epithelial cells. In SIV infection of macaques, villous atrophy is a very early event; however, it is accompanied by crypt cell hyperproliferation. Early- and late-stage enteropathy in immunodeficiency virus infection may represent two types of immunologically mediated mucosal transformation in which the number and state of activation of regulatory T cells determine whether hypo- or hyperproliferative villous atrophy occurs.