Although mycophenolate mofetil (MMF) monotherapy has been successfully used in liver transplant recipients suffering from calcineurin‐inhibitor (CNI)‐related chronic toxicity, still no consensus has been reached on its safety, efficacy and tolerability. We attempted the complete weaning off CNI in 42 individuals presenting chronic renal dysfunction and/or dyslipidemia and/or arterial hypertension and simultaneously introduced 1.5 gm/day MMF. CNI could be completely withdrawn in 41 cases. A total of 32 (75%) patients are currently on ≤1.5 gm/day of MMF. Mean follow‐up from the introduction of MMF is 31.5 months and mean length of follow‐up from the beginning of MMF monotherapy is 27.3 months. Renal function improved in 31/36 (89%) cases. Blood levels of cholesterol and triglycerides decreased in 13 of 17 (76%) and 15 of 17 (89%) patients, respectively. Arterial hypertension improved in 4 of 5 (80%) cases. A total of 8 patients showed a single episode of fluctuation of liver function tests during tapering off CNI. This feature was interpreted as an acute rejection (AR), based on the resolution of the clinical setting after escalation of MMF daily dose to 2 gm. A further patient developed a biopsy‐proven AR insensitive to MMF adjustment, requiring reinstitution of the CNI dose. No deaths or major toxicity requiring MMF discontinuation occurred. In conclusion, low dose MMF monotherapy is safe, effective, and well tolerated. Liver Transpl, 2007. © 2006 AASLD.