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Introduction: Propofol is an IV anesthetic with rapid onset and short duration of action, making it a preferred agent for sedation in critically ill patients. Propofol’s use within the pediatric population is limited due to concern for propofol-related infusion syndrome (PRIS), a rare but potentially fatal complication with manifestations including metabolic acidosis, lactic acidosis, and rhabdomyolysis. Thus, propofol infusions are often limited to < 48 hours in children. However, data on the safety of prolonged propofol use in the PICU remains limited. This study aimed to determine the incidence of PRIS or associated features in critically ill children receiving propofol infusions >48 hours. Methods: We conducted a single-center, retrospective observational study of pediatric patients admitted to the PICU who received continuous propofol infusions for ≥48 hours between January 2019 and December 2023. Data was collected by chart review and included demographics, propofol infusion duration and dosing, relevant lab values (lactate, creatine kinase, triglycerides), and clinical outcomes. PRIS was defined using clinical and laboratory criteria. Results: Seventy-nine patient encounters met the inclusion criteria. The median infusion duration was 75 hours, with a maximum of 445 hours. Median peak CK was 118 U/L, triglycerides 214 mg/dL, and lactate 1.8 mmol/L. No patients met full criteria for PRIS, and only one patient developed rhabdomyolysis in the setting of status epilepticus. Spearman’s rank correlation showed no significant association between infusion duration and peak lactate (ρ=0.4491), CK (ρ=0.9426), or triglycerides (ρ=0.1858). Comparing patients on propofol for 48–72 hours versus ≥72 hours using the Kruskal-Wallis test revealed no significant differences (p=0.5, 0.6, and 0.2, respectively). Conclusions: In this 5-year retrospective study, propofol infusions exceeding 48 hours were not associated with PRIS. Mild lab abnormalities occurred, but clinically significant adverse effects were rare. There was no correlation found between infusion duration and laboratory markers linked to PRIS. These findings suggest that with close monitoring, prolonged propofol infusions may be safe in select pediatric patients. Prospective studies are needed to guide risk stratification and clinical practice.