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We report the two-year follow-up of a trial comparing the three-month postgraft discontinuation of either cyclosporine (CsA) or mycophenolate mofetil (MMF) from a triple-drug regimen after de novo renal transplantation.One hundred and eight patients were enrolled in this study and randomized to be withdrawn from CsA (MMF group, n=54) or MMF (CsA group, n=54).Despite an increased risk of acute rejection and a lower, but nonsignificant, two-year graft survival, CsA withdrawal induced a sustained improvement of the renal function. At one year, the chronic allograft damage index was similar in both the MMF and CsA groups. However, CsA elimination resulted in a higher incidence of C4d deposits, irrespective of the occurrence of a prior acute rejection. While this finding could suggest a risk of chronic rejection in the MMF group, the outcome did not appear to be related to the C4d status. Moreover, logistic regression analysis showed that only two factors, acute rejection and the one-year glomerular filtration rate level, were predictive of a significant decline of the renal function at two years.These results point out the need to secure the minimization of the calcineurin inhibitors after renal transplantation, in order to reduce the risk of acute rejection in these patients, because this strategy allows the improvement of the one-year renal function which is predictive of a chronic allograft dysfunction.