Infusion of a simianized anti-alpha(4)beta(7) mAb (Rh-alpha(4)beta(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-alpha(4)beta(7) in combination with cART was found to lead to prolonged viral suppression after withdrawal of all therapeutic interventions. The humanized form of Rh-alpha(4)beta(7), vedolizumab, is a highly effective treatment for inflammatory bowel disease. To clarify the mechanism of action of Rh-alpha(4)beta(7), naive macaques were infused with Rh-alpha(4)beta(7) and sampled in blood and tissues before and after treatment to monitor several immune cell subsets. In blood, Rh-alpha(4)beta(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-alpha(4)beta(7) did not impact integrin alpha(4)(+) cells, but decreased the frequencies of CCR6(+) and CD69(+) CD4(+) T cells and, in the gut, Rh-alpha(4)beta(7) transiently decreased the frequency of memory and IgA(+) B cells. In summary, even in the absence of inflammation, Rh-alpha(4)beta(7) impacted selected immune cell subsets in different tissues. These data provide new insights into the mechanisms by which Rh-alpha(4)beta(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.