Background-Effective immunosuppression is a critical determinant of organ and patient survival in cardiac transplantation. The present study was designed to determine the potency of FTY720, a new synthesized immunosuppressant, and examine its clinical potential as an immunosuppressant. Methods and Results-Hearts of DBA/2 mice were transplanted heterotopically in C57BL/6 mice. Recipients were treated with oral FTY720 in doses of 0.3, 1, 3, or 10 mg. kg(-1). d(-1) or with 40 mg. kg(-1). d(-1) of cyclosporin A (CsA) as a comparative treatment. The median graft survival time (MST) was significantly prolonged by treatment with FTY720 10 mg. kg(-1). d(-1). MST was not prolonged by FTY720 1 mg. kg(-1). d(-1) or CsA. However, FTY720 1 mg. kg(-1). d(-1) combined with CsA 40 mg. kg(-1). d(-1) resulted in a significant prolongation of MST. Histopathological studies performed 5 days after transplantation demonstrated remarkable suppression of inflammatory response by treatment with FTY720 10 mg. kg(-1). d(-1). Interleukin (IL)-2 and interferon (IFN)-gamma production was not suppressed; however, cytotoxic T lymphocyte activity was strongly suppressed in vitro. In addition, IL-2-stimulated T-cell proliferation and class I and class II MHC antigen expression on IFN-gamma-stimulated macrophages were strongly inhibited by FTY720. Histopathological studies 60 days after transplantation (DBA/2-B10.D2) demonstrated a beneficial effect on graft atherosclerosis. Conclusions-FTY720 promoted long-term cardiac graft survival and strongly inhibited the progression of graft atherosclerosis. These observations suggest that FTY720 has a promising clinical potential in cardiac transplantation.