The purpose of the study was to introduce mycophenolate mofetil (MMF) in liver transplant recipients with renal dysfunction to decrease calcineurin inhibitor (CNI) dosages without increasing rejection risk. In this prospective, multicenter, randomized study, chronic CNI-related renal dysfunction was defined by an increase in serum creatinine with values >140 μmol/L and <300 μmol/L. Patients were randomized in 2 groups. Study group: combination of MMF (2 to 3 g/day) and reduced dose of CNI ≥50% of initial dose; control group: no MMF, but with the ability to reduce CNI doses, but not below 75% of initial dose. Fifty-six patients were included, 27 in the study group and 29 in the control group. In the study group, there was a significant decrease in serum creatinine values, from 171.7 ± 24.2 μmol/L at day 0 to 143.4 ± 19 μmol/L at month 12 and a significant increase in creatinine clearance, from 42.6 ± 10.9 mL/min to 51.7 ± 13.8 mL/min. No rejection episode was observed in the study group. In the control group, there was no improvement of renal function, assessed by the changes in serum creatinine values, from 175.4 ± 23.4 μmol/L at day 0 to 181.6 ± 63 μmol/L at month 12, and in creatinine clearance, from 42.8 ± 12.8 mL/min to 44.8 ± 19.7 mL/min. The differences between the 2 groups were significant: P = 0.001 for serum creatinine, and P = 0.04 for creatinine clearance. In conclusion, the introduction of MMF combined with the reduction of at least 50% of CNI dose allowed the renal function of liver transplant recipients to significantly improve at 1 year, without any rejection episode and without significant secondary effects. Liver Transpl 12:1755–1760, 2006. © 2006 AASLD.