Cord blood transplantation is being used with increasing frequency for patients with high-risk hematologic malignancies. Myeloablative preparative regimens provide antitumor efficacy and facilitate engraftment but are associated with higher morbidity and nonrelapse mortality rates than nonablative regimens. We evaluated 3 sequential myeloablative regimens in the cord blood transplant setting. Regimen 1 (melphalan, fludarabine, and thiotepa) produced prompt engraftment and minimal engraftment failure but was associated with a high nonrelapse mortality rate. Regimen 2 (busulfan and fludarabine) was very well tolerated but was associated with a high rate of engraftment failure and relapse. Regimen 3 (busulfan, clofarabine, fludarabine, and low-dose total body irradiation given 9 days after the chemotherapy) was associated with a low rate of engraftment failure but was logistically difficult to administer. Finally, regimen 3 that included the total body irradiation given immediately after the chemotherapy was well tolerated, with prompt engraftment and tumor control. This latter regimen appears to be effective in preliminary studies and warrants further evaluation.