ABSTRACT:   Background: Pegaspargase (PEG-ASP) and calaspargase pegol (CAL-PEG) are long acting asparaginase formulations used to treat acute leukemia. As of December 2022, CAL-PEG became the standard formulation for pediatric patients less than 22 years of age. The objective of this study was to compare real-world safety and efficacy of the two formulations in pediatric patients at a single institution.       Procedure: A three-year retrospective evaluation of PEG-ASP and CAL-PEG utilization was completed. Patients treated at stand-alone children’s hospital for acute leukemia who received at least one dose of long acting asparaginase therapy were included. Incidence and severity of hypersensitivity reactions, silent inactivation, thromboembolism, bleeding, pancreatitis, hepatotoxicity, and hypertriglyceridemia were collected.   Results: A total of 103 patients were included, of whom 50 received CAL-PEG and 58 received PEG-ASP. In the CAL-PEG group, 10 patients experienced a symptomatic hypersensitivity reaction, compared to six patients in the PEG-ASP group (20.0% vs. 10.3%; p = 0.16). Eight patients receiving CAL-PEG had a silent inactivation while compared to three patients receiving PEG-ASP (16.0% vs. 5.2%; p = 0.18). There was a higher rate of hyperbilirubinemia noted with PEG-ASP compared to CAL-PEG (58.6% vs. 34.0%; p = 0.01). Other adverse effects, including hypertriglyceridemia, thrombosis, bleeding, transaminitis, and pancreatitis were comparable between the two groups.     Conclusions: There were no significant differences found between CAL-PEG and PEG-ASP in terms of hypersensitivity reactions and silent inactivation. Most other adverse effects associated with asparaginase therapy were also similar between the two groups. Monitoring and preventative measures should continue for patients to help prevent the adverse effects associated with CAL-PEG.