We examined the kinetics of intestinal intraepithelial lymphocytes (IEL) and the incidence of apoptosis at villus or crypt sites during the development of non-irradiated acute graft-versus-host disease (GVHD). The first IEL to increase were host-origin on day 3 and the donor-derived IEL appeared first on day 12 after GVHD induction. Unique CD3+CD4+CD8 alpha/alpha+ IEL were significantly increased on day 6 and an appreciable number of IEL bearing T cell receptor V beta capable of recognizing self-superantigen were detected on day 9. The sudden appearance of apoptosis and reduction of mitotic activity occurred on day 12, accompanied by a dramatic decrease of CD3+CD4-CD8 alpha/alpha+ IEL of host origin. CD8 alpha/alpha+ IEL of host origin, which expand and then decrease by apoptosis at the early stage of acute GVHD, may be associated with pathogenesis of the enteropathy occurring during acute GVHD.