Background: Intravenous recombinant enzyme replacement therapy (ERT) is currently available for 8 lysosomal diseases. Hypersensitivity reactions (HSRs) may be observed during this long-term treatment. Objective: To evaluate the frequency and clinical treatment features of ERT HSRs and the management of desensitizations in children. Methods: Medical records were reviewed retrospectively for patients who received ERT. Those who had experienced HSRs to ERT were included in the study. The demographic characteristics of the patients, culprit enzyme, signs and symptoms, diagnostic tests, management of the reaction, and the protocol employed for the maintenance of ERT were recorded. Results: During the study period, 54 patients received ERT in our institution. A total of 11 patients (20.4%) experienced HSR to ERT. All reactions were of immediate type. The most common symptoms were cutaneous manifestations. A total of 9 patients experienced urticaria, and 2 had anaphylaxis as initial reaction. Patients who had isolated cutaneous symptoms continued their treatments with antihistamines, corticosteroid premedication, slower infusion rate or both. Patients who had recurrent urticaria with these modalities or those who had anaphylaxis continued their ERT with desensitization (n = 8). A total of 3 patients required revisions in desensitization protocols because of recurrent anaphylaxis. Conclusion: The reactions that develop during this long-term treatment may be treated by premedication-prolonged infusion, but in some patients, desensitization protocols are necessary for the continuation of therapy. Revisions in desensitization protocols may be required.