Children with sickle cell disease (SCD) are at risk for neurocognitive impairment and poor academic achievement, although there is limited research on factors predicting academic achievement in this population. This study explores the relative contribution to academic achievement of a comprehensive set of factors, such as environmental (socioeconomic status), disease-related (stroke, transfusion therapy, adherence), and psychosocial variables (child behavior, child quality of life (QoL)), controlling for intellectual functioning (IQ). Eighty-two children with SCD completed measures assessing IQ and academic achievement, while parents completed questionnaires assessing adherence, child behavior, and child quality of life. Medical chart reviews were conducted to determine disease-related factors. Hierarchical regression analyses indicated that 55% of the variance in academic skills was accounted for by IQ, parent education, chronic transfusion status, and QoL [R = .55, F(5, 77) = 18.34, p < .01]. Follow-up analyses for broad reading [R = .52, F(5, 77) = 16.37, p < .01], and math calculation [R = .44, F(5, 77) = 12.14, p < .01] were also significant. The findings suggest a significant contribution of factors beyond IQ to academic achievement. Findings allow for identification of children with SCD at risk for academic difficulties for whom psychoeducational interventions may enhance academic achievement.