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Calcineurin inhibitors (CNIs) are the cornerstone of immunosuppression after liver transplantation. However, CNI treatment is frequently associated with chronic renal failure (CRF). The reduction or interruption of CNI may reduce renal failure. We prospectively studied 49 liver recipients treated with CNI (tacrolimus, n = 14; cyclosporine, n = 35) who secondarily developed CNI-associated CRF and for whom mycophenolate mofetil (MMF) was introduced to reduce or withdraw CNI. The creatinine clearance (CCl; 42.9 ± 14 ml/minute) increased significantly after CNI reduction (48.8 ± 17 ml/minute after 1 year, 49.9 ± 18 ml/minute after 2 years, and 58.4 ± 20 ml/minute after 3 years, P < 0.0001). CCl decreased during the 2 years before CNI reduction at a rate of −5.6 ± 5 ml/minute/year; for the 2 years after CNI reduction, CCl increased significantly by +3.2 ± 4.3 ml/minute/year (P < 0.0001). Ten patients did not have improved renal function after 1 year, but the rate of decrease in CCl slowed after CNI reduction. Three parameters were identified as risk factors for unresponsiveness to CNI reduction: (1) low CCl at MMF introduction, (2) a high rate of CCl decrease during the 2 years before conversion, and (3) alcoholic cirrhosis. The type of CNI molecule used did not impair the renal response. None of the patients developed acute or chronic graft rejection after the reduction or interruption of CNI. In liver recipients with CRF, a reduction or withdrawal of CNI concomitantly with the introduction of MMF was safe and was associated with an improvement in renal function. Liver Transpt 13:1004–1010, 2007. © 2007 AASLD.