OBJECTIVES: Allogeneic hematopoietic stem cell transplantation (HSCT) can cure Sickle Cell Disease (SCD) but traditional chemotherapy-based conditioning regimens for HSCT are associated with substantial morbidity and mortality. The objective of this study was to determine if an innovative approach of chemotherapy-free, non-myeloablative HSCT with alemtuzumab is associated with improved health-related quality of life (HRQoL) in adult SCD patients. METHODS: Thirteen high-risk SCD patients underwent chemotherapy-free HSCT at a large urban academic medical center using human leukocyte antigen (HLA)-matched, related donors. Indications for transplantation in this cohort included frequent pain crises, stroke, and/or ≥2 lifetime episodes of acute chest syndrome. Generic HRQoL was assessed using the SF-36 in 9 patients who were assessed pre-HSCT and at 365 post-HSCT.  Magnitude of effect was evaluated for SF-36 norm-based subscales and the SF-6D summary scores based on standardized response mean (SRM) (SRM>0.5=medium; SRM>0.8=large effect). RESULTS: Of 13 patients, all survived and 9 had completed 365 day post-HSCT assessments by time of analysis.  Mean change scores 365-day post-HSCT were 4.6 (SD 21.3) for physical functioning (PF) (SRM_PF=0.2), 9.0 (SD 23.0) for role physical (RP) (SRM_RP=0.4), 17.1 (SD 14.2) for bodily pain (BP) (SRM_BP=1.20), 18.6 (SD 16.0) for general health (GH) (SRM_GH=1.16), 15.2 (SD 10.5) for vitality (VT) (SRM_VT=1.45), 13.0 (SD 17.2) for social function (SF) (SRM_SF=0.76), 5.1 (SD 14.7) for role emotional (RE) (SRM_RE=0.34), 5.7 (SD 9.8) for mental health (MH) (SRM_MH=0.59) and 0.21 (SD 0.13) forSF-6D index score (SRM_SF6D=1.66).    CONCLUSIONS: Our pilot study demonstrated a large magnitude of improvement in HRQoL in terms of BP, GH, VT and overall health according to the SF-6D for SCD patients undergoing chemotherapy-free, non-myeloablative HSCT with alemtuzumab.  These promising results, which are the first report of the impact of this innovative treatment on HRQoL in adults, warrant further investigation with more patients under treatment and longer-term follow-up.