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BACKGROUND: Asparaginase agents are vital in the treatment of acute lymphoblastic leukemia (ALL) and can be delivered via an intravenous (IV) or intramuscular (IM) injection. Hypersensitivity reaction (HSR) rates with these agents are common, multifactorial, and treatment-altering. The specific route of asparaginase administration may lead to disparate rates of HSRs and other adverse events in pediatric patients with ALL. OBJECTIVE: To analyze the role of administration route in the incidence and severity of adverse events in pediatric patients receiving asparaginase therapy. METHODS: This single-center, retrospective analysis evaluated patients receiving pegaspargase or Erwinia asparaginase from January 1, 2008, through September 30, 2015. The primary outcome measured the incidence of HSRs with IV or IM pegaspargase and IV or IM Erwinia asparaginase. Secondary outcomes included the potential role of administration route on the timing and rate of adverse drug events. RESULTS: A total of 368 patients received pegaspargase during the study period. Of this group, 199 received only IV pegaspargase, 138 received only IM pegaspargase, and 31 received both IV and IM pegaspargase. Overall, HSRs occurred in 18.6% of patients who received IV administration and 13.8% who received IM administration (P = .241). Among patients who received both routes during ALL treatment, 9.7% had an HSR. A total of 43 (76.8%) patients had an HSR during the consolidation phase of therapy. A total of 517 Erwinia asparaginase doses were administered, and only 1 patient had an HSR. We found increased antiemetic use in 28 (36.4%) of 77 IV Erwinia asparaginase doses compared with only 28 (6.4%) of 440 IM doses (P <.001). CONCLUSION: Our findings showed no significant difference in HSR rates between patients receiving IV pegaspargase and those receiving IM pegaspargase. Hypersensitivity resulting from Erwinia asparaginase were infrequent, and IV Erwinia asparaginase administration displayed more emetogenicity than the traditional IM route. [ABSTRACT FROM AUTHOR]