Results of allogeneic hematopoietic stem cell transplantation (HCT) to treat advanced leukemia or myelodysplastic syndrome (MDS) remain poor due to excessive relapse and transplant-related mortality. To improve transplant outcome in this patient population, 43 patients (median age, 46.1 years) with high-risk or advanced lymphoid (n = 5) or myeloid malignancy (n = 38) were prospectively enrolled on a pilot trial of cytoreduction with intravenous busulfan and melphalan followed by an unmodified HLA-A, -B, and -DRbeta1-matched related (n = 18) or unrelated (n = 25) HCT. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. Thirty-four patients had > or = 5% blasts at the time of HCT; 12 of these had > 20% blasts. Seventeen patients had unfavorable cytogenetics, 8 patients underwent transplantation for secondary MDS or acute myelogenous leukemia, and 4 patients had relapsed after a previous allogeneic transplantation. Although mucositis was the most significant regimen-related toxicity, requiring the addition of folinic acid rescue and failure to receive all 4 doses of methotrexate in 23 patients, the nonrelapse mortality at 30 and 100 days was low at 0% and 16%, respectively. The cumulative incidence of grade II-IV acute GVHD was 24%, and that of extensive chronic GVHD was 7%. With a minimum follow-up of 18 months, the estimated 3-year overall survival is 37% and the estimated disease-free survival (DFS) is 33%. For 18 patients with MDS (< or = RAEB-2) or high-risk myeloproliferative disorder, the estimated 3 year DFS is 61%. These data demonstrate the curative potential of this regimen in patients with high-risk myeloid malignancies.