The outcome of 55 patients who underwent matched unrelated donor (MUD) transplantation for acute myelogenous leukemia (AML) following a conditioning regimen of cyclophosphamide and total-body irradiation (TBI) with the addition of Alemtuzumab 10 mg/kg/day on days -5 to -1 is described. All patients received graft-versus-host disease (GVHD) prophylaxis with cyclosporine as well as 3 doses of posttransplant methotrexate. Forty-one patients were transplanted in complete remission (CR) (20 in CR1, 20 in CR2, and 1 in CR3), and 14 were not in remission at the time of transplantation as they were refractory to chemotherapy either at induction or at relapse. The group consisted of adult patients with a median age of 37 years. Thirty-five patients were fully matched at HLA-A, -B, -C, and -DRB1. All patients engrafted and there were no cases of graft rejection. Grade II-IV acute GVHD occurred in only 2 patients. Chronic GVHD developed in 30% of patients but was extensive in only 3 cases. The predicted TRM was 11% at day 100 and 26% at 1 year. In multivariate analysis the receipt of an HLA mismatched transplant was associated with a higher transplant-related mortality (TRM) (55% versus 15%). Twelve of the 14 transplant-related deaths were due to infection. The 5-year cumulative incidence of relapse was 36% for the whole group and 28% for patients in CR at transplantation. The 5-year cumulative survival for the whole group was 38% and was 49% for those in remission at transplantation. Seven of the 12 patients transplanted in CR1 with adverse risk cytogenetics remain alive and in remission, and the predicted 5-year overall survival (OS) for this group is 50%. These results support the use of Alemtuzumab for unrelated donor hematopoietic stem cell transplant (HSCT) for poor risk AML in CR1 and for relapsed AML in CR2. The addition of Alemtuzumab is highly effective in preventing both rejection and severe acute and extensive chronic GVHD without an increased relapse risk.