Sickle cell disease (SCD) results in neuropsychological complications that place adolescents at higher risk for limited educational achievement. A first step to developing effective educational interventions is to understand the impact of SCD on school performance. The current study assessed perceptions of school performance, SCD interference and acceptability of educational support strategies in adolescents with SCD. To identify potential risk factors, the relationships between school performance, SCD interference and demographics were also examined. Thirty adolescents aged 12 to 20 years completed demographics and SCD school performance questionnaires. Approximately 37% of participants reported receiving special education services, but more than 60% reported that SCD interfered with their school performance. Females reported that SCD impacted their schooling more than males (?[superscript 2] (1, n = 30) = 5.00, p < 0.05). Study findings provide important insights into demographic risk factors and support the need for individualized health and educational plans for adolescents with SCD.