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The self-care management of sickle cell disease (SCD) improves mortality rate; however, compliance with SCD self-care management remains a problem. The purpose of this study was to examine the knowledge and factors that influence compliance with SCD self-care management recommendations among caregivers of children with SCD. The health belief model was used as the theoretical foundation of this study, theorizing that caregivers' perceived susceptibility, severity, and benefits of SCD self-care management will influence compliance. The study used a quantitative research design. A cross-sectional survey was administered to 100 caregivers of children with SCD attending sickle cell clinics in Lagos, Nigeria using convenience sampling. Information was obtained from participants using a structured interviewer-administered questionnaire, and data were analyzed using descriptive statistics, bivariate correlations, and binary logistic regression techniques. Findings confirmed a high adherence rate but low knowledge of SCD self-care management among the caregivers of children with SCD. There was no significant correlation between knowledge of SCD self-care management and adherence. However, the findings from the multivariate analysis identified knowledge as a predictor of adherence and religiosity and total number of barriers as barriers to adherence. Parental health beliefs did not influence adherence to SCD self-care management. These findings have social change implications by guiding the work of health educators, health care providers, and public health practitioners to incorporate group counseling on SCD self-care management at every sickle cell clinic.