Background: Reduced intensity conditioning followed by allogeneic hematopoietic stem cell transplantation can often be curative for the treatment of hemoglobinopathies. Procedure: This is a prospective IRB-approved (NCT02435901) clinical trial, reporting the possible impact of “late” alemtuzumab (administered on days -10 to-8) versus “early” alemtuzumab (-19 to -17) with respect to engraftment and acute/chronic graft-vs-host disease (GvHD) in a group of 35 pediatric patients with sickle cell disease (SCD) or thalassemia undergoing bone marrow transplantation (BMT) following conditioning with alemtuzumab, fludarabine and melphalan. The first 9 patients with SCD received “late” alemtuzumab followed by BMT from HLA matched siblings (MSD). The next 26 patients (21 with SCD and five thalassemia major) received “early” alemtuzumab. Of the 26 patients, 17 received transplant from MSD and nine from matched unrelated donors (MUD). Results: In the “late” group, one patient (11%) developed acute GvHD, six (67%) achieved sustained engraftment. Three patients (33%) ultimately experienced graft rejection, leading to early termination of enrollment of patients on this regimen. In the “early” alemtuzumab group, acute and chronic GvHD developed in 50% and 34% patients, respectively none of the patients experienced graft rejection. Three patients died, 2 due to GvHD-related complications and 1 from sepsis. Five patients developed stable mixed chimerism while 14 demonstrated 100% donor chimerism at one year post-transplant and beyond. Conclusions: These results suggest a benefit with respect to engraftment of administering “early” vs “late” alemtuzumab in this RIC regimen but with the possible cost of an increase in acute, and possibly chronic GvHD.