Chronic red cell transfusion (CRCT) therapy is one of few disease-modifying treatments for sickle cell disease (SCD). This study evaluated health-related quality of life (HRQL) in children receiving CRCT relative to 2 comparison groups: children with similar, severe SCD and children with milder disease risk defined by SCD genotype. For this study, 67 children with SCD between the ages of 8 and 18 completed the self-report Pediatric Quality of Life Sickle Cell Disease module (PedsQL SCD) as part of a pilot clinical program during routine hematologic visits. A medical chart review was also performed. Linear regression suggested that children in the CRCT group had significantly higher self-reported HRQL ratings for domains related to pain, F 2,64 =4.07 (P=0.022) and pain-related functioning, F 2,64 =4.32 (P=0.017), compared with children with similar and milder disease risk. Exploratory analyses implied that children in the CRCT group also had fewer worries about SCD-related complications, F 3,63 =9.68 (P<0.001). These patient-perceived benefits of CRCT may have important implications for treatment decisions and for providing ancillary support for children with SCD and their families.