Background: Pegaspargase (PEG-ASP) is essential chemotherapy for acute lymphoblastic leukemia (ALL). Since changing to intravenous (IV) administration from intramuscular (IM), an increased number of allergic reactions have been anecdotally noted at our institution. This study compares the rate and severity of allergic reactions in children receiving IM or IV PEG-ASP., Methods: We performed a retrospective chart review of patients treated with IV or IM PEG-ASP at The Hospital for Sick Children, Toronto, Canada, from March 1, 2010 to January 1, 2012. The incidence and severity of allergic reactions attributed to PEG-ASP were documented. Patient age, sex, route of PEG-ASP administration, disease (risk group and lineage) and mean time interval between PEG-ASP doses were evaluated as possible risk factors for allergic reaction., Results: A total of 109 patients were included. There were 14 (35 %) allergic reactions among 40 patients who received IV, compared with eight (12 %) of the 69 who received IM [odds ratio (OR) 4.11, 95 % confidence interval (CI) 1.54-10.97, p = 0.005]. In multivariable logistic regression adjusting for disease risk group, route (IV vs. IM) remained independently significant (p = 0.011). Patients with standard-risk ALL had a lower risk of experiencing an allergic reaction associated with PEG-ASP compared with patients in high-risk disease risk groups (collectively referred to as "other"; 11 vs. 31 %, OR 3.36, 95 % CI 1.16-9.72, p = 0.025)., Conclusions: IV PEG-ASP is associated with a significantly higher rate of allergic reactions than IM. The clinical preference for IV PEG-ASP may warrant re-evaluation.