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Little is known about the relationships among self-efficacy, social determinants of health, and health outcomes in adults living with sickle cell disease (SCD). We conducted mediation analyses examining the relationships among health literacy, perceived stigma, self-efficacy, and health outcomes in an online cohort of adults living with SCD. The health outcomes explored were physical and mental health-related quality of life (HRQOL) and pain interference; covariates included gender, disease severity, and depressive symptoms. Data came from a cross-sectional, descriptive study of 60 adults with SCD. Perceived stigma and self-efficacy had significant relationships with the study outcomes, while health literacy did not. Self-efficacy partially mediated the relationship between perceived stigma and physical HRQOL, when controlling for depressive symptoms. Future research should investigate the influence of stigma and self-efficacy on health outcomes in patients with SCD and consider stigma when creating interventions to modify self-efficacy.