Conditioning regimens contribute significantly to outcomes following allogeneic stem cell transplantation (allo-SCT). Reduced-intensity conditioning (RIC) regimens provide lower toxicity at the cost of reduced efficacy compared with myeloablative conditioning (MAC) regimens. However, because pre-transplant prognostic variables often determine the conditioning regimen, studies of RIC vs. MAC have been inconclusive. We present a retrospective analysis of 242 acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) patients, 112 of whom were in 56 pairs matched using propensity scores, to account for variation that may confound clinical outcomes. The uniform conditioning regimens consisted of fludarabine with pharmacokinetic (PK)-guided intravenous busulfan (Bu). The RIC and MAC regimens were dosed at the average daily area under the concentration-vs-time curve (AUC) of 4000 µMol min and 5000–6000 µMol min, or total course AUC of 16,000 µMol min and 20,000–24,000 µMol min, respectively; PK-guided dosing removes overlap in systemic Bu exposure. When patients’ data were propensity-matched, there was a trend toward significantly increased full donor chimerism and decreased chronic graft vs. host disease in RIC, and no significant differences in progression free survival and overall survival between RIC and MAC. Our results also elucidate the efficacy of PK-guided-dosing in the setting of allo-SCT for AML and MDS.