Any role for reduced-intensity conditioning (RIC) prior to hematopoietic cell transplantation (HCT) from a human leukocyte antigen (HLA)-haploidentical donor remains to be defined. We therefore assessed 83 patients (age, 16-70 years), 68 with acute leukemia, including 34 in remission and 34 with refractory disease; and 15 patients with myelodysplastic syndrome, in HCT trials utilizing RIC with busulfan, fludarabine, and anti-thymocyte globulin. The HLA-haploidentical donors, either offspring (n=38), mothers (n=24), or siblings (n=21) of patients, underwent leukapheresis after receiving granulocyte colony-stimulating factor and donated cells were transplanted without further manipulation. Cyclosporine and methotrexate were given for graft-versus-host disease (GVHD) prophylaxis. The cumulative incidences of neutrophil engraftment, grade 2-4 acute GVHD, chronic GVHD, and transplantation-related mortality after HCT, were 92%, 20%, 34%, and 18%, respectively. After a median follow-up time of 26.6 months (range, 16.8-78.8 months), the event-free and overall survival rates were 56% and 45%, respectively, for patients with acute leukemia in remission; 9% and 9%, respectively, for patients with refractory acute leukemia; and 53% and 53%, respectively, for patients with myelodysplastic syndrome. HCT from an HLA-haploidentical family member resulted in favorable outcomes when RIC containing anti-thymocyte globulin was performed. This study is registered at www.clinicaltrials.gov as #NCT00521430 and #NCT00732316.