The Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) performed a prospective multicenter study of TCR-αβ/CD19-depleted haploidentical HCT in children with acute leukemia and myelodysplastic syndrome (MDS) to determine 1-year disease free survival (DFS) and compare 2-year outcomes to other donor cell sources. Fifty-one patients 0.7-21 years old were enrolled; donors were killer immunoglobulin-like receptor (KIR)-favorable based upon ligand mismatch and/or high B-content. The 1-year DFS was 78% (95% CI 66-89%). Superior 2-year DFS and OS were noted in patients <10 years of age, those treated with reduced toxicity conditioning (RTC) rather than traditional myeloablative conditioning, and children who were flow minimal residual disease (MRD) <0.01% pre-transplant. Multivariate analysis comparing the KIR-favorable haploidentical cohort with concomitantly enrolled Center for International Blood and Marrow Transplant Research (CIBMTR) controls showed similar DFS and OS compared to other donor cell sources. Multivariate analysis also showed a marked decrease in the risk of grade 2-4 (p=0.0001) and 3-4 acute GHVD (p=0.0062), chronic GVHD (p<0.0001), and transplant related mortality (TRM; p<0.0001) vs. other donor cell sources. Ethnic and racial minorities accounted for 53% of enrolled patients, and data from a large cohort of recipients/donors screened for KIR showed that >80% of recipients had a KIR-favorable donor by our definition, demonstrating that this approach is broadly applicable to groups often unable to find donors. This prospective, multicenter study showed improved outcomes using TCR-αβ/CD19-depleted haploidentical donors using RTC for children with acute leukemia and MDS; randomized trials comparing this approach with matched unrelated donors are warranted (ClinicalTrials.gov NCT02646839).