We prospectively compared outcomes after a fludarabine (Flu) plus oral busulfan (Bu)-containing reduced-intensity conditioning regimen (150 mg/m2 Flu and 10 mg/kg oral Bu), with (n = 32; Flu- T Bu group) or without (n = 30; Flu-Bu group) therapeutic dose monitoring and dose adjustment of Bu. All patients received peripheral blood stem cells from a genoidentical sibling, and study cohorts had similar patient characteristics. Dose adjustments of Bu were required in 20 (63%) patients in the Flu- T Bu group (median final dose, 8.89 mg/kg; range, 6.3-13.34 mg/kg). Donor T-cell and granulocyte engraftments were similar, and early conditioning-related toxicities were mild and similar in both study groups. With a median follow-up of 45 months (51 months in the 37 survivors), posttransplantation outcomes did not differ between cohorts. The strongest predictor of 2-year overall survival and leukemia-free survival was the presence of chronic graft-versus-host disease (77% versus 34% for overall survival and 74% versus 34% for leukemia-free survival; P < .001 for both outcomes). In conclusion, therapeutic dose monitoring of oral Bu in a reduced-intensity conditioning setting does not seem to affect outcome, although further studies may identify very-high-risk patients who benefit from this strategy.