Refined graft-versus-host disease (GVHD)/relapse-free survival (GRFS) considers main outcomes of allogeneic stem cell transplant (HSCT), estimating long-term survival without significant morbidity as a surrogate of HSCT success. We compared GRFS in 5059 adults with acute myeloid leukemia (AML), undergoing HSCT in first complete remission from 2000 to 2015 either from a matched sibling (MSD, n = 3731) or unrelated donor (MUD, n = 1328). Median age was 49 (range: 18–76) years. Median follow-up was 32 and 60 months in MSD and MUD, respectively (p < 0.01). Compared to MSD, at 4 years, MUD recipients had lower GRFS, with higher NRM, grade III–IV acute GVHD, and extensive chronic GVHD (HR: 1.42, p < 0.01). We also performed a risk factor analyses, showing unfavorable cytogenetics (HR: 1.42, p < 0.01) and peripheral blood as stem cell source (HR: 1.22, p < 0.01) associated to lower GRFS, while this was higher with in vivo T-cell depletion (TCD, HR: 0.73, p < 0.01) and shorter time from diagnosis to HSCT (HR 0.96, p < 0.01). Different factors, modifiable or not, such as donor type, stem cell source, disease biology, and in vivo TCD, impact on GRFS and this may guide in the future transplant choices to improve morbidity and long-term quality of life.