The gastrointestinal (GI) mucosa is central to HIV pathogenesis, and the integrin α₄β₇ promotes the homing of immune cells to this site, including those that serve as viral targets. Data from simian immunodeficiency virus (SIV) animal models suggest that α₄β₇ blockade provides prophylactic and therapeutic benefits. We show that pre-HIV infection frequencies of α₄β₇⁺ peripheral blood CD4⁺ T cells, independent of other T cell phenotypes and genital inflammation, were associated with increased rates of HIV acquisition in South African women. A similar acquisition effect was observed in a Kenyan cohort and in nonhuman primates (NHPs) after intravaginal SIV challenge. This association was stronger when infection was caused by HIV strains containing V2 envelope motifs with a preference for α₄β₇ binding. In addition, pre-HIV α₄β₇⁺ CD4⁺ T cells predicted a higher set-point viral load and a greater than twofold increased rate of CD4⁺ T cell decline. These results were confirmed in SIV-infected NHPs. Increased frequencies of pre-HIV α₄β₇⁺ CD4⁺ T cells were also associated with higher postinfection expression of lipopolysaccharide binding protein, a microbial translocation marker, suggestive of more extensive gut damage. CD4⁺ T cells expressing α₄β₇ were rapidly depleted very early in HIV infection, particularly from the GI mucosa, and were not restored by early antiretroviral therapy. This study provides a link between α₄β₇ expression and HIV clinical outcomes in humans, in line with observations made in NHPs. Given the availability of a clinically approved anti-α₄β₇ monoclonal antibody for treatment of inflammatory bowel disease, these data support further evaluation of targeting α₄β₇ integrin as a clinical intervention during HIV infection.