Neointima formation as a result of smooth muscle cell (SMC) proliferation still contributes significantly to venous bypass graft stenosis and failure. The new immunosuppressive agent FK778 has recently been shown to exert anti-proliferative effects. We examined the inhibitory potential of FK778 on venous SMC proliferation and neointima formation in an experimental venous bypass graft model. Quiescent venous SMCs were incubated for 48 h with 10% FCS and different concentrations of FK778. SMC proliferation was measured by Ki67 immunostaining. Uridine was added to reverse FK778 induced pyrimidine synthesis blockade. The effect of FK778 treatment on neointima formation in vivo was assessed in an autologous epigastric vein-to femoral artery interposition graft model in rats. In vitro, FK778 inhibited venous SMC proliferation in a dose dependent manner. This effect was reversed by addition of uridine. In vivo, 3-week oral treatment with FK778 (15 mg/kg/d) significantly reduced neointima formation and stenosis in venous bypass grafts. We show that the immunosuppressive agent FK778 can prevent neointima formation in experimental venous bypass grafts by inhibiting venous SMC proliferation. FK778 might provide a new pharmacological therapy to limit vein graft stenosis and bypass graft failure.