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Acute chest syndrome (ACS) is a common cause of death in sickle cell disease (SCD) patients. Multiple studies investigated the risk factors of developing ACS; however, predictors of recurrent ACS episodes have not been thoroughly investigated. We aim to examine the clinical and laboratory predictors of recurrent ACS in pediatric patients with SCD. A retrospective case-control study included pediatric patients with SCD (˂14 years) admitted with ACS or developed ACS during admission for another indication. Patients were classified into recurrent ACS episodes (≥2 episodes) and a single ACS episode groups. Ninety-one ACS episodes (42 patients) were included, with a mean age at diagnosis of 7.18 ± 3.38 years. Twenty-two (52.4%) patients were male, and twenty-five (59.5%) patients had recurrent ACS. Younger age at first ACS was significantly associated with recurrence (p = 0.003), with an optimal cutoff at 7.5 years (area under the receiver operating characteristic curve [AUROC] = 0.833; p < 0.001). Higher SCD-related hospitalizations were significantly associated with recurrence (p = 0.038). Higher mean values of baseline white blood count (WBC) (p = 0.009), mean corpuscular volume (MCV) (p = 0.011), and reticulocyte (p = 0.036) were significantly associated with recurrence. Contrarily, lower baseline hematocrit values (p = 0.016) were significantly associated with recurrence. The ACS frequencies were significantly lower after hydroxyurea (p = 0.021). The odds of ACS recurrence increased with a positive C-reactive protein (CRP) at admission (p = 0.006). In conclusion, several baseline and admission laboratory data showed significant associations with recurrence. Hydroxyurea therapy demonstrated reduced ACS episodes.