The α4β7 integrin plays a central role in the homing of T cells to the gut. We hypothesized that absence of the β7 subunit would result in a reduction of intestinal graft-versus-host disease (GVHD) and an improvement in overall GVHD morbidity and mortality in recipients of hematopoietic stem cell transplantation (HSCT). Analysis of alloreactive β7^-/- T cells showed intact activation, proliferation, cytokine production, and cytotoxicity. However, recipients of β7^-/- donor T cells in murine HSCT models experienced less GVHD morbidity and mortality than recipients of wild-type (WT) T cells, associated with a decrease in donor T-cell infiltration of the liver and intestine and with an overall significant decrease in hepatic and intestinal GVHD. In graft-versus-tumor (GVT) experiments, we demonstrated intact or even enhanced GVT activity of β7^-/- donor T cells. In conclusion, β7^-/- donor T cells caused less GVHD morbidity and mortality than WT donor T cells because of selectively decreased T-cell infiltration of the liver and intestines. Our data suggest that strategies to target the β7 integrin have the clinical potential to alleviate or prevent GVHD while sparing or potentiating GVT activity.