Myeloablative doses of BU and fludarabine followed by allogeneic hematopoietic cell transplantation offer effective therapy for AML. We anticipated that pharmacokinetic targeting of i.v. BU to 5300 μM/L min/day × 4 (targeted i.v. BU and fludarabine (t-i.v. BU/Flu)) would limit nonrelapse mortality (NRM) in adults up to 70 years of age. We assessed the safety and efficacy of t-i.v. BU/Flu in a series of 100 adults (median age 48, range 22-69 years) with AML in the first CR (CR1) with high risk of treatment failure (n=49), second CR (CR2, n=25), relapsed disease (REL, n=9), primary induction failure (PIF, n=16) and untreated (n=1). NRM was 3% at 100 days and 15% at 1 year. The cumulative incidence of relapse was 30.6% for CR1, 41.7% for CR2, 55.6% for REL and 58.6% for PIF. OS for primary AML in CR1 was 66% (95% confidence interval (CI): 46-80%) at 1 year, and 62% (95% CI: 42-77%) at 2 years. On multivariable modeling, remission status, moderate/severe chronic GVHD and day-90 BM chimerism ≥90% predicted improved OS. Importantly, there was no effect of age. t-i.v. BU/Flu provides effective disease control with encouraging NRM in patients up to age of 70 years.