Infusion of a simianized anti-α_4β_7 mAb (Rh-α_4β_7) just before and following SIV infection protected rhesus macaques from developing AIDS and partially from vaginal SIV acquisition. Recently, short-term treatment with Rh-α_4β_7 in combination with cART was found to lead to prolonged viral suppression after withdrawal of all therapeutic interventions. The humanized form of Rh-α_4β_7, vedolizumab, is a highly effective treatment for inflammatory bowel disease. To clarify the mechanism of action of Rh-α_4β_7, naive macaques were infused with Rh-α_4β_7 and sampled in blood and tissues before and after treatment to monitor several immune cell subsets. In blood, Rh-α_4β_7 increased the CD4^+ and CD8^+ T cell counts, but not B cell counts, and preferentially increased CCR6^+ subsets while decreasing CD103^+ and CD69^+ lymphocytes. In mucosal tissues, surprisingly, Rh-α_4β_7 did not impact integrin α_4^+ cells, but decreased the frequencies of CCR6^+ and CD69^+ CD4^+ T cells and, in the gut, Rh-α_4β_7 transiently decreased the frequency of memory and IgA^+ B cells. In summary, even in the absence of inflammation, Rh-α4_β_7 impacted selected immune cell subsets in different tissues. These data provide new insights into the mechanisms by which Rh-α_4β_7 may mediate its effect in SIV-infected macaques with implications for understanding the effect of treatment with vedolizumab in patients with inflammatory bowel disease.