Abstract Vaso-occlusive episodes (VOEs) are a major concern in patients with sickle cell disease (SCD). Exposure to systemic corticosteroids has been suspected to increase the occurrence of VOEs in case reports or series. No comparative study has been conducted to investigate this risk, which is still debated. Several clinical trials demonstrated the effectiveness of corticosteroids for the treatment of VOEs, but with increased rates of readmission. The aim of the study was to assess the risk of hospitalization for VOE associated with exposure to systemic corticosteroids in patients with SCD. We used a case-case-time-control design in a nationwide population-based cohort built in the French national health insurance database between 2010 and 2018. The population included all patients with SCD with at least 1 hospitalization for VOE. Corticosteroids were identified using out-of-hospital dispensing data. The outcome was the first hospitalization for VOE. The case-case-time-control design induces self-adjustment for time-invariant confounders, including genotype. Analyses were adjusted for time-dependent confounders (infections, red blood transfusions) and stratified by exposure to hydroxyurea. Overall, 5151 patients were included in the main analysis. Corticosteroid exposure was significantly associated with the occurrence of hospitalizations for VOEs: adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.4-5.6). In patients exposed to hydroxyurea, the adjusted odds ratio was 2.6 (95% CI, 1.1-6.4); it was 4.0 (95% CI, 2.5-6.3) in unexposed patients. These results were consistent in children and adults. In conclusion, systemic corticosteroids were associated to an increased risk of hospitalization for VOEs and should be limited in patients with SCD.