Background.Chronic rejection is the leading cause of long-term allograft loss. Until now, no therapy has been recognized as being efficient in its prevention. In addition to their immunosuppressive activity, mycophenolate mofetil (MMF) and rapamycin (RAPA) show diverse properties against vascular smooth muscle cell activity, cell-adhesion molecule expression, and ischemia-reperfusion injury. The combination effect of MMF and RAPA was tested to prevent chronic renal allograft rejection in the rat in this study.Methods.Nephrectomized Lewis recipients underwent orthotopic transplantation with Fisher (F344) kidneys (allograft groups) or Lewis kidneys (isograft control). The initial episode of acute rejection was controlled with a short course of cyclosporine A (CsA) (1.5 mg/kg/day for 10 days). From weeks 4 to 20, animals were thereafter treated every other day either with vehicle, MMF (20 mg/kg), RAPA (0.8 mg/kg), or MMF (20 mg/kg) plus RAPA (0.8 mg/kg) in combination. Animals were sequentially killed at serial intervals over a follow-up of 50 weeks, and histologic study was performed on harvested kidneys according to the Banff working classification for allograft pathology.Results.Animals treated with MMF or RAPA alone showed a Banff sum score similar to the allograft control group (6.31±1.01 and 7.27±1.14 vs. 7.21±1.14, respectively;P>0.05). When the recipient rats were treated with MMF and RAPA in combination, it resulted in a clinically and statistically significant reduction of Banff sum score (4.21±0.79,P<0.01), with specific inhibition of vascular fibrous intimal thickening, allograft glomerulopathy, and interstitial fibrosis.Conclusion.Over a 50-week study, concomitant therapy of MMF and RAPA prevents chronic renal allograft rejection, probably through reduction of ischemic and cytotoxic degenerative changes. These results warrant further investigation in the combination of MMF and RAPA as anti–chronic rejection therapy in clinical transplantation.