Background: Adequate oxygen saturation (SpO 2 ) is crucial for managing sickle cell disease (SCD). Children with SCD are at increased risk for occult hypoxemia; therefore, understanding SpO 2 threshold practices would help identify barriers to oxygen optimization in a population sensitive to oxyhemoglobin imbalances. We investigated SpO 2 cutoff levels used in clinical algorithms for management of acute SCD events at children's hospitals across the United States, and determined their consistency with recommended national guidelines (SpO 2 > 95%)., Methods: Clinical pathways and algorithms used for the management of vaso-occlusive crisis (VOC) and acute chest syndrome (ACS) in SCD were obtained and reviewed from large children's hospitals in the United States., Results: Responses were obtained from 94% (140/149) of eligible children's hospitals. Of these, 63 (45%) had available clinical algorithms to manage VOC and ACS. SpO 2 cutoff was provided in 71.4% (45/63) of clinical algorithms. Substantial variation in SpO 2 cutoff levels was noted, ranging from ≥90% to more than 95%. Only seven hospitals (5% of total hospitals and 15.6% of hospitals with clinical algorithms available) specified oxygen cutoffs that were consistent with national guidelines. Hospitals geographically located in the South (46.8%; n = 29/62) and Midwest (54.8%; n = 17/31) were more likely to have VOC and ACS clinical algorithms, compared to the Northeast (26.5%; n = 9/34) and West (36.4%; n = 8/22)., Conclusion: There is inconsistency in the use of clinical algorithms and oxygen thresholds for VOC and ACS across US children's hospitals. Children with SCD could be at risk for insufficient oxygen therapy during adverse acute events., (© 2024 Wiley Periodicals LLC.)