We reported that T cell receptor (TcR) gamma delta intestinal intraepithelial lymphocytes (i-IEL) of host origin increased transiently, then decreased drastically at the early stage of non-irradiated acute graft-versus-host disease (GVHD) in mice. We investigated the role of the TcR gamma delta i-IEL of host origin in the pathogenesis of the intestinal lesions that occur during acute GVHD. The acute GVHD was induced in mice which had been depleted of TcR gamma delta by in vivo administration of hamster monoclonal antibody (mAb) against TcR gamma delta. Although the degree of splenomegaly after the induction of acute GVHD in mice treated with anti-TcR gamma delta mAb was similar to that in control mice treated with hamster anti-2,4,6-trinitrophenyl mAb, infiltration of donor-derived T cells into the epithelium, and mitosis and apoptosis of crypt cells in the intestinal mucosa were dramatically suppressed in these mice. This suggest that host TcR gamma delta T cells in i-IEL contribute to the development of enteropathy in acute GVHD in mice.