Mucopolysaccharidosis type VI (MPS VI) is a progressive, chronic, and multisystem lysosomal storage disease. Enzyme replacement therapy (ERT) with the recombinant human arylsulfatase B enzyme (galsulfase [Naglazyme]) is recommended as first-line therapy. It is generally reported as safe and well tolerated. Frequently observed mild to moderate infusion-related reactions which can be easily handled by reducing or interrupting the infusion and/or administering additional antihistamines, antipyretics, and corticosteroids are mostly mediated by non-IgE mechanisms. Here we report two children with MPS VI who experienced IgE-mediated reactions with galsulfase at the second year of the therapy. One child had anaphylaxis and the other had urticarial eruptions. They could receive ERT after successful rapid desensitization. To our knowledge, this is the second report on galsulfase allergy with IgE-mediated reaction. It is important to recognize IgE-mediated reactions since they can be life-threatening and do not respond to the standard therapies. We recommend allergy skin tests in the evaluation of infusion-related reactions unresponsive to standard therapies, so that continuation of ERT will be feasible after successful desensitization.