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Determining how the health-related quality of life (HRQOL) is impacted by living with Sickle Cell Disease (SCD) can inform psychosocial interventions. The purpose of the present study is to determine if demographic and treatment variables predict membership into empirically derived subgroups of HRQOL among youth and young adults with SCD. Three hundred and seven youth and young adults with SCD (mean 17.63 years ± 3.74 years, 50.5% female) completed the Pediatric Quality of Life InventoryTM Sickle Cell Disease Module. Latent profile analy