Background. Acute chest syndrome (ACS) is a life-threatening complication of sickle cell disease (SCD). Most often ACS occurs during progression of painful vasoocclusive crisis (VOC) in vulnerable patients. Study objective was to describe early risk factors for ACS progression focusing on patients’ assessment in pediatric Emergency Department. Methods. In this retrospective case-control study (years 2016 to 2022), patients with SCD who presented VOC progressing to ACS were compared to patients who presented uncomplicated VOC. Medical history, clinical and laboratory data were collected for both groups. Statistical correlations and logistic regression model were established. Results. A total of thirty-one children with ACS (median age at inclusion 2 years [ 0 – 3.9], 32% females, 55 ACS) were matched with the same number of children with uncomplicated VOC (median age at inclusion 3 years [ 0 – 5.2], 32% females, 55 VOC). ACS occurrence was positively correlated with diffuse (multifocal) pain, decreased nutritional status (Body Mass Index (BMI), weight/expected weight for age ratio, weight /expected weight for height ratio), hydroxyurea treatment, red cell distribution width (RCDW) and C-Reactive protein (CRP) plasma concentration, and negatively correlated with SC phenotype, A-Rhesus positive blood group, and lower limbs pain (p<0.05). Logistic regression model defined two early risk factors for ACS occurrence: decreased BMI (in percentiles for age and gender) and elevated CRP (p<0.05). Conclusions. Undernutrition in children with SCD is involved in ACS pathophysiology and should be prevented. Early systemic inflammation during an acute painful crisis (VOC) is predictive for ACS occurrence.