To identify disease-related risk factors and psychosocial resistance factors that impact adherence to prescribed treatment in the context of admission to a Hematology Acute Care Unit (HACU) designed to provide acute care for children with sickle cell disease (SCD) presenting with pain or fever. A total of 73 primary caregivers and 24 children (if age 8 or older) completed standardized forms during the HACU admission. Treatment adherence variables (medical staff rating, SCD-related care activities, percentage of agreement between treatment recommendations made and care activities, and attendance at hematology clinic) indicated moderate-to-high adherence. Based on regression analyses, the risk variable of disease-related stress and the resistance variables of family flexibility and less reliance on passive coping accounted for significant portions of the variance in treatment adherence. Empirical evaluation of interventions designed to improve communication regarding expectations for the care of children with SCD and to support active family problem solving during times of SCD-related stress must be ongoing.