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Mycophenolate Mofetil (MMF) has been shown to significantly decrease the number of acute rejection episodes in renal transplant recipients during the 1st year. A beneficial effect of MMF on long-term graft survival has been more difficult to demonstrate. This beneficial effect has not been detected, despite the impact of acute rejection on the development of chronic allograft nephropathy and experimental evidence that MMF may have a salutary effect on chronic allograft nephropathy independent of that of rejection.Data on 66,774 renal transplant recipients from the U.S. renal transplant scientific registry were analyzed. Patients who received a solitary renal transplant between October 1, 1988 and June 30, 1997 were studied. The Cox proportional hazard regression was used to estimate relevant risk factors. Kaplan-Meier analysis was performed for censored graft survival.MMF decreased the relative risk for development of chronic allograft failure (CAF) by 27% (risk ratio [RR] 0.73, P <0.001). This effect was independent of its outcome on acute rejection. Censored graft survival using MMF versus azathioprine was significantly improved by Kaplan-Meier analysis at 4 years (85.6% v. 81.9%). The effect of an acute rejection episode on the risk of developing CAF seems to be increasing over time (RR=1.9, 1988–91; RR=2.9, 1992–94; RR=3.7, 1995–97).MMF therapy decreases the risk of developing CAF. This improvement is only partly caused by the decrease in the incidence of acute rejection observed with MMF; but, is also caused by an effect independent of acute rejection.