BackgroundL‐Asparaginase is an effective drug in the treatment of childhood acute lymphoblastic leukemia (ALL). The use of L‐asparaginase may be limited by serious adverse events of which allergy is the most frequent. The objective of this study was to describe the clinical aspects of PEG‐asparaginase allergy in children treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol.ProcedureChildren (1–17 years) enrolled in the NOPHO ALL2008 protocol between July 2008 and August 2011, who developed PEG‐asparaginase allergy were identified through the NOPHO ALL2008 toxicity registry. In the NOPHO ALL2008 protocol, patients are randomized to 8 or 15 doses of intramuscular PEG‐asparaginase (Oncaspar®) 1,000 IU/m2/dose administered at 2 or 6 weeks intervals during a total period of 30 weeks. (Clinical trials.gov no: NCT00819351).ResultsOf 615 evaluable patients, 79 patients developed clinical PEG‐asparaginase allergy (cumulative risk; 13.2%) and discontinued PEG‐asparaginase therapy for that reason. PEG‐asparaginase allergy occurred after a median of two doses (75% range 2–4, max 14). In 58% of PEG‐asparaginase hypersensitive patients, the clinical allergic reactions appeared within 2 hr after PEG‐asparaginase administration and ranged from mild symptoms to systemic anaphylaxis. Nine patients experienced an anaphylactic reaction within 1 hr and 50 min from asparaginase administration; none were fatal. Four of 68 patients (6%) who subsequently received Erwinase therapy also reacted allergic to Erwinase.ConclusionClinical allergy to PEG‐asparaginase occurred early in treatment, was in general moderate in severity, and mostly developed within 2 hr after PEG‐asparaginase administration. The risk of subsequent Erwinase allergic reactions was low. Pediatr Blood Cancer 2015;62:427–433. © 2014 Wiley Periodicals, Inc.