Background: While many advances have been made in the understanding of Sickle Cell Disease (SCD) in the past decades, the natural history of the disease is often elusive due to lack of long-term prospective data collection (1). The SCD Natural History Study is a longitudinal follow-up study. During the 15 years of the study, the Italian Association of Pediatric Hematology Oncology (AIEOP) guidelines were used to standardize treatment with Hydroxyurea (HU), red blood cell transfusion and Hematopoietic Stem Cell Transplantation (HSCT) as well as management of acute and chronic complications (2). Aims: To describe mortality, chronic morbidity and intensity of treatments in a pediatric natural history cohort. Methods: Since 2007 all pediatric patients with SCD followed in the Pediatric SCD Reference Center of Padua were enrolled. Data on physical examination, acute/chronic complications and laboratory parameters were prospectively recorded at every outpatient and inpatient visit since diagnosis. Results: 197 children and adolescents with SCD were enrolled and 182 patients had clinical, hematological and organ damage monitoring information as of 31/12/2020. The mean follow-up is 79.8 months (range 2.1-298.6) (IQR 36.9-126.3). Females were 51%, mean age at diagnosis was 39.0 months (range 0-228.4), with only 31% diagnosed before the first year of life and 18% before the 2nd year, due to the lack of national universal newborn screening. 83% were HbSS/SB°, 14.8% SC, 2.2% SB +; 83% came from Sub-Saharan Africa, 9.3% from Europe. 44.5% had chronic comorbidities, the most frequent being: neurological manifestations, asthma and wheezing, gallbladder stones. As of 12/31/2020, 117 were in follow-up and treatment, 57 had transferred abroad or to other national centers, 4 had been lost to follow-up and 4 deceased (3 due to Pneumococcus septic shocks, 1 for a trauma accident). 67% of children required disease-modifying therapies in various combinations (44% HU, 2.2% transfusion regimen, 10% HU and transfusions, 10.8% HSCT after having performed HU and/or transfusion regimen) showing the need for intensive treatments to control the symptoms of the disease (mainly recurrent Vaso-Occlusive Crisis or Acute Chest Syndrome, Anemia or Cerebral Vasculopathy); 16/182 required enrollment in clinical trials with new drugs due to lack of persistent response to HU or chronic transfusion. The treatment with HU, although prescribed according to the national guidelines only to children with clinical manifestations (for anemia, VOC or ACS), was effective in increasing Hemoglobin (9 vs 8.3 g/ dl, p <0, 0001), reducing hemolysis indices and lowering the incidence of neurological complications overall (abnormal/conditional TCD or presence of silent cerebral infarcts on MRI or stenosis on MRA) with EFS 89.1 (95% CI 81.2-93.8) in those who performed HU within 5 years of diagnosis vs 65.6 (95% CI 51.2-76.6) in those who did not (p<0,0001) (Figure 1).However, 11% of the children still present significant neurological complications 5 years after diagnosis in spite of undergoing HU, thereby in need of more intensive treatment to reduce the cerebrovascular complications which in our cohort appear to develop early. Conclusion: Long-term data collection in our setting indicates that, in spite of being offered highly specialized monitoring and treatment options, a subgroup of children still displays significant organ damage and would require intensified treatment in early age.