The burden of sickle cell disease (SCD) in France has been difficult to apprehend due to the paucity of reliable nationwide epidemiological data. We aimed to describe the epidemiology of SCD and evaluate its burden and costs. Patients with SCD and most severely affected patients were identified between 2012 and 2018 from the French National Health Data System database (SNDS, Système national des données de santé). Outcomes of interest included rates of acute and chronic complications, healthcare resource utilization and associated costs, and were compared in subpopulations of patients before and after hematopoietic stem cell transplantation, initiating hydroxyurea or a chronic transfusion program. Between 2012 and 2018, 22,619 patients with SCD were identified, among which 4,270 patients were defined as most severely affected. Rates of vaso-occlusion episodes and acute chest syndrome were 86.29 (95% confidence interval [CI]: 85.75-86.83] and 12.90 (95% CI: 12.69-13.11) per 100 person years in the study population and 166.9 (95% CI: 165.4- 168.4) and 22.71 (95% CI: 22.16-23.27) per 100 person years in most severely affected patients. Median (Q1-Q3) annualized total costs were €5,073.63 (range, €1,633.74-14,000.94) and €13,295.67 (range, €5,754.67-26,385.23) in the study population and most severely affected patients. Median annualized costs were ten times lower after treatment intensification for hematopoietic stem cell transplantation (€29,011.75 vs. €2,465.98; P<0.001), they slightly decreased after hydroxyurea initiation (€13,057.79 vs. €12,752.44; P=0.003) and were five times higher after chronic transfusion program initiation (€4,643.11 vs. €22,715.85; P<0.001). SCD still places a significant demand on health resources, even after therapeutic intensification.