Cyclosporine A (CsA) alone or in combination with mycophenolate mofetil (MMF) has been used as graft-versus-host-disease (GvHD) prophylaxis since the development of reduced intensity conditioning (RIC). The association of CsA+MMF, while commonly used after transplantation from a matched unrelated donor (MUD), has never been tested in a large randomized prospective trial. We retrospectively investigated the outcomes of 497 adult patients with AML in complete remission (CR) undergoing a MUD transplant between 2007-2017 using CsA+MMF or CsA alone as GvHD prophylaxis, and registered with the ALWP of the EBMT. Patients had CsA alone (n=183) or CsA+MMF (n=314) as GvHD prophylaxis. All underwent a RIC regimen with fludarabine and busulfan and received anti-thymocyte globulin. The median age at transplant was similar (59 and 60 years in the CsA and CsA+MMF group). The median follow-up was not significantly different between the two groups (33 vs 34 months in CsA and CsA+MMF, respectively). Disease status at transplant was first complete remission (CR1) for 81% in CsA group and 86% in CsA+MMF group (p=NS). Peripheral blood stem cells (PBSC) was the graft source in 93% of patients receiving CsA alone and in 96% of patients who received CsA+MMF (p=0.17). All but 2 patients engrafted. The 100 day cumulative incidence (CI) of grade II-IV and grade III-IV acute GvHD were 30% and 10%, respectively. The 2-year CI of chronic GvHD was 35% and CI of extensive cGvHD was 15%. The 2-year CI of non-relapse mortality (NRM) and relapse were 19% and 25%, respectively. Disease recurrence (n=31), GvHD (n=20) and infection (n=17) were the most common causes of death in the CsA group. Relapse (n=53), GvHD (n=28) and infection (n=28) were the most frequent causes of death in the CsA+MMF group. The 2-year GVHD-free relapse-free survival (GRFS), leukemia- free survival (LFS), and overall survival (OS) were 45%, 56% and 60%, respectively. On multivariate analysis (MVA), no statistically significant differences between the two groups with respect to relapse, NRM, LFS, OS, acute and chronic GvHD were identified. A positive cytomegalovirus serology of the donor was associated with higher NRM [HR=2.03, p In a subgroup analysis in patients in CR1 who received PBSC, no differences were detected between the two groups for relapse, NRM, LFS, OS, or aGvHD. Patients who received CsA alone tended to have a higher cGvHD (p=0.05). However, this finding was not statistically significant in MVA. We observed comparable outcomes in AML patients in CR1 who underwent MUD transplantation and RIC with CsA+MMF or CsA alone as GvHD prophylaxis. This suggests that both strategies may be considered valid approaches. Randomized trials are needed to further assess which patients could benefit from the addition of MMF in GvHD prophylaxis