Lymphocyte Peyer patch adhesion molecule (LPAM) or alpha(4)beta(7) integrin is expressed on lymphocytes and is responsible for T-cell homing into gut-associated lymphoid tissues through its binding to mucosal addressin cell adhesion molecule (MAdCAM), which is present on high endothelial venules of mucosal lymphoid organs. We found in murine allogeneic bone marrow transplantation (BMT) models that recipients of alpha(4)beta(7)(-) donor T cells had significantly less graft-versus-host disease (GVHD) morbidity and mortality compared with recipients of alpha(4)beta(7)(+) donor T cells. A kinetic posttransplantation analysis of lymphocytes in the intestines and mesenteric lymph nodes demonstrated a delayed invasion of lower numbers of alpha(4)beta(7)(+) T cells in recipients of alpha(4)beta(7)(-) T cells compared with recipients of alpha(4)beta(7)(+) T cells. Histopathologic analysis of GVHD target organs revealed that recipients of alpha(4)beta(7)(-) T cells developed less GVHD of the intestines and liver, whereas there was no difference in cutaneous and thymic GVHD between recipients of alpha(4)beta(7)(-) or alpha(4)beta(7)(+) T cells. Finally, we found that in vivo GVT activity of alpha(4)beta(7)(-) donor T cells was preserved. We conclude that the alpha(4)beta(7) integrin is important for the invasion of alloreactive donor T cells into the gut and the subsequent development of intestinal GVHD and overall GVHD morbidity and mortality.