Children with sickle cell disease (SCD) experience organ damage, impaired quality of life, and premature mortality. Allogeneic bone marrow transplantation from an HLA-matched sibling can halt disease progression but is limited by donor availability. A multicenter phase II trial conducted from 2008-2014 enrolled 30 children aged 4-19 years; 29 were eligible for evaluation. The primary objective was 1-year event-free survival (EFS) after HLA allele-matched (at HLA-A, -B, -C and -DRB1 loci) unrelated donor transplantation. Conditioning regimen included alemtuzumab, fludarabine, and melphalan. Graft-versus-host disease (GVHD) prophylaxis included calcineurin inhibitor, short course methotrexate and methylprednisolone. Transplant indications included stroke (N=12), trans-cranial Doppler velocity >200 cm/second (N=2), >/=3 vaso-occlusive pain crises/year (N=12) or >/=2 acute chest syndrome episodes (N=4) in the 2 years preceding enrollment. Median follow up was 26 months (range 12-62); graft rejection was 10%. One and 2-year EFS were 76% (95% CI 56-88) and 69% (95% CI, 48-82), respectively. The corresponding rates for overall survival (OS) were 86% (95% CI 67-95) and 79% (95% CI 59-90). The day-100 incidence of grade II-IV acute GVHD was 28% (95% CI 13-45); 1-year incidence of chronic GVHD was 62% (95% CI 41-77); 38% classified as extensive. There were 7 GVHD-related deaths. A 34% incidence of posterior reversible encephalopathy syndrome was noted in the first 6 months. Although the 1-year EFS met the pre-specified target of >/=75%, this regimen cannot be considered sufficiently safe for widespread adoption without modifications to achieve more effective GVHD prophylaxis. The trial is registered to https://clinicaltrials.gov as NCT00745420.