In the current study, we have analyzed the efficacy of cyclosporine A (CSA) plus mycophenolate mofetil (MMF) as graft-versus-host disease (GVHD) prophylaxis in the fludarabine plus melphalan or busulfan reduced intensity regimen (RIC) setting in a series of 44 patients receiving allogeneic transplantation from an unrelated donor. Only 23% were in the first complete remission at the time of transplant. Cumulative incidence of grades II-IV and III-IV acute GVHD (aGVHD) was 53% and 23%, respectively. Fifty-six percent had equal to or greater than grade 2 gut involvement. Cumulative incidence of overall and extensive chronic GVHD (cGVHD) was 93% and 63%, respectively. Ninety-two percent of patients who were evaluable +100 days after transplant were in complete remission. Relapse rate was 25% at 2 years. Event free (EFS) and overall survival (OS) at 2 years were 52%. Pharmacokinetic assays of mycophenolic acid (MPA) showed a therapeutic area under the curve (AUC) at the dosage of 3 g daily, although a large inter- and intraindividual variations of MPA plasma levels were found. In conclusion, the combination of CSA plus MMF in the fludarabine plus melphalan or busulfan RIC setting is feasible. Regarding GVHD, this combination allowed to control aGVHD but lead to a high incidence of cGVHD, so that newer strategies are required, especially in trying to decrease gastrointestinal involvement.