BACKGROUND: Alemtuzumab-containing conditioning regimens are used for allogeneic hematopoietic stem cell transplantation (HSCT) to reduce acute and chronic graft-versus-host disease (GVHD) and the risk of graft rejection. Alemtuzumab is typically administered intravenously but is often accompanied by infusion-related side effects, including injection site reactions and anaphylaxis. Little is known about the routes of administration and if they differ in safety and efficacy in pediatric patients, especially when used in transplant conditioning. OBJECTIVES: To compare adverse effects and efficacy outcomes between intravenous and subcutaneous alemtuzumab administration in pediatric patients with sickle cell disease who have undergone HSCT. STUDY DESIGN: A retrospective cohort of 49 pediatric patients with sickle cell disease aged 4-16 years underwent HSCT and received either intravenous or subcutaneous alemtuzumab at St. Louis Children's Hospital or Phoenix Children's Hospital. The incidence of infusion-related reactions, neutrophil and platelet recovery, graft failure, and immune reconstitution were compared. RESULTS: We found that subcutaneous alemtuzumab administration elicited fewer infusion-related reactions than intravenously administered drug (p = 0.038). No significant differences in engraftment rates, graft failure rates, infectious complications, acute GVHD, and immune reconstitution were found between the two groups. CONCLUSION: Subcutaneous administration of alemtuzumab for children undergoing transplant for sickle cell disease is safe and effective.