The development of graft coronary arteriosclerosis remains a serious consequence after heart transplantation and may limit long-term survival. The purpose of this study was to evaluate the effects of 15-Deoxyspergualin on graft coronary arteriosclerosis after heterotopic heart transplantation in a rat model and compare the effects to those of cyclosporine treatment. Two groups of Lewis rats (n = 7 each group) underwent heterotopic heart transplantation from Fischer 344 donors and were treated with either cyclosporine (10 mg/kg/day) or 15-Deoxyspergualin (3 mg/kg/day). Histologic evaluations of rejection (scale: 0 = none, 3 = severe) and graft coronary arteriosclerosis (scale: 0 = normal, 4 = occluded) were made 60 days after transplantation. No significant difference was found between the two groups with respect to the degree of rejection (2.0 +/- 0.7 in the cyclosporine-treated group versus 2.0 +/- 0.5 in the 15-Deoxyspergualin-treated group). However, the extent of graft coronary arteriosclerosis in the 15-Deoxyspergualin-treated group was significantly less than that seen in the cyclosporine-treated group (1.11 +/- 0.34 versus 1.71 +/- 0.24, p < 0.01). Furthermore, the incidence of diseased vessels among all observed vessels was significantly lower in the 15-Deoxyspergualin-treated group compared with the cyclosporine-treated group (63% +/- 12% versus 76% +/- 7%, p < 0.05). Although the protective mechanism of 15-Deoxyspergualin is unknown, it most likely possesses a different immunosuppressive mechanism of action from cyclosporine. We concluded that 15-Deoxyspergualin is superior to cyclosporine in preventing graft coronary arteriosclerosis after heart transplantation.