We hypothesized that standardized systemic drug delivery would improve treatment safety and provide better leukemia control. We therefore developed an intravenous busulfan formulation and combined it with fludarabine instead of cyclophosphamide in preparation for allogeneic stem cell transplantation (alloSCT). We used a Bayesian method to compare the outcomes of 67 acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) patients who received intravenous busulfan-cyclophosphamide (BuCy2) with 148 subsequent AML/MDS patients who received busulfan-fludarabine (Bu-Flu). The groups had comparable pretreatment characteristics, except that the Bu-Flu patients were older, more often had unrelated donors and had a shorter follow-up. A greatly improved outcome in the Bu-Flu group is unlikely to be explained by improved supportive care during this time period. Overall, the data support replacing BuCy2 with or without antithymocyte globulin (ATG) with Bu-Flu with or without rabbit-ATG for AML or MDS. We further suggest that the high level of safety and fast recovery from conditioning therapy-related side effects after the Bu-Flu regimen makes it a suitable platform technology for testing additional adjuncts for improved posttransplant immune recovery and long-term disease control in patients who are at high risk of rapidly recurrent disease after alloSCT. The extremely low one-year treatment-related mortality as well as high overall and event-free survival of patients in the Bu-Flu group indicate that it is time to revisit the value of alloSCT compared with conventional maintenance chemotherapy for patients in first complete remission of AML/MDS.