Cytoprotective genes have shown to display potent anti-inflammatory and antiapoptotic functions in endothelial and smooth muscle cells. We investigated whether cytoprotective genes, especially A20, were involved in mycophenolate mofetil (MMF)'s ability to ameliorate transplant arteriosclerosis in an experimental chronic rejection model. Sprague-Dawley rat renal grafts were orthotopically transplanted into Wistar rats following the procedure of Kamada with our modification. The recipients were divided into three oral treatment groups: (1) vehicle group (cyclosporine [CsA] 10 mg/kg.d x 10 d followed by vehicle), (2) CsA group (CsA 10 mg/kg.d x 10 d followed by CsA 6 mg/kg.d), (3) MMF group (converted from CsA 10 mg/kg.d x 10 d to MMF 20 mg/kg.d on day 11). At the same time points after transplantation, the rats were sacrificed to harvest the renal allografts. The expression of four cytoprotective genes, A20, heme oxygenase (HO)-1, Bcl-2, and Bcl-XL, was analyzed by quantitative reverse-transcriptase polymerase chain reaction and immunohistochemistry. The four-cytoprotective genes were all detected in rat kidney allografts undergoing chronic allograft nephropathy. The expression of A20 in grafted kidneys was significantly higher in the MMF than in the CsA or the vehicle group (P < .01). There was no significant difference between the CsA and the MMF groups in the expression of HO-1, Bcl-2, and Bcl-XL. We demonstrated that MMF improved the expression of A20 in rat kidney allografts undergoing chronic allograft nephropathy. The correlation between MMF and A20 provide an explanation for the mechanism by which MMF ameliorates transplant arteriosclerosis in an experimental animal model of chronic rejection.