Hematopoietic cell transplantation is the only curative therapy for patients with myelodysplasia (MDS). However, treatment-related toxicity and, in patients with advanced MDS (RAEB, RAEB-T) and those who have transformed to AML (tAML), post-transplant relapse continues to be problematic. We reviewed results in 128 patients with advanced MDS and tAML transplanted from HLA-identical related or unrelated donors after preparation with myeloablative conditioning regimens. Seventy-eight patients were conditioned with busulfan (Bu), prescribed dose 16 mg/kg, adjusted to achieve plasma concentrations of 800-900 ng/ml, plus cyclophosphamide (Cy), 2 x 60 mg/kg [tBuCy], and 50 patients were conditioned with Bu 7 mg/kg (without dose adjustment) and total body irradiation (TBI) 6 x 200 cGy given over 3 days [BuTBI]. There was no statistically significant difference in regards to overall survival, relapse-free survival (RFS), or non-relapse mortality (NRM) between the 2 regimens regardless of donor status. However, there was a trend towards higher rates of relapse (HR 1.33, P=0.38) and lower rates of NRM (HR 0.61, P=0.09) in patients conditioned with tBuCy. The increased rate of relapse seen with tBuCy was significant when restricted to only those patients with a diagnosis of RAEB (HR 4.50, P=0.02). Patients given BuTBI had a higher incidence of GvHD; however, the incidence of GvHD regardless of grade did not differ significantly between patients who relapsed and those who did not. Thus, in patients with advanced MDS/tAML, the use of a less toxic conditioning regimen resulted in a non-significant overall gain in RFS largely due to lower rates of NRM. New concepts of conditioning regimens are needed which reduce toxicity without increasing the risk of relapse.