Both rejection and graft-versus-host-disease may occur after fully allogeneic small bowel transplantation. In this study, we established unidirectional models of rejection and GVHD in rats and evaluated the efficacy of 15-deoxyspergualin (DSG). When F1 small bowel was transplanted into LEW rats (rejection model) the graft was acutely rejected. The administration of DSG (5 mg/kg per day for 10 days) significantly prolonged the survival, but was efficacious only when used prophylactically. When a unidirectional GVHD model (F1 --> LEW SBTx) was examined, the administration of DSG from day 0 after grafting greatly suppressed GVHD, resulting in more than 300 days survival. However, only cutaneous GVHD, but not fatal GVHD, was suppressed when the start of administration was postponed until day 4 after grafting. From in vitro studies, DSG inhibited natural killer cell activities to K-562 and skin epidermal cells. The response was well correlated with in vivo GVHD course. These results suggest that DSG is an effective immunosuppressant for both rejection and GVHD when used prophylactically. DSG exerted the effect more stongly against cutaneous GVHD than fatal GVHD by inhibiting natural killer systems.