Mucopolysaccharidosis (MPS) II is an X-linked metabolic disorder caused by dysfunction of iduronate-2-sulfatase (I2S). This abnormality causes the progressive accumulation of incompletely degraded glycosaminoglycans (GAGs) in the lysosomes. The auditory characteristics of MPS II in mouse models have not been reported. In this study, we evaluated the auditory characteristics of the MPS II in IDS knock-out (IDS-KO) mice. In addition, the effect of enzyme replacement therapy (ERT) on hearing was studied. The IDS-KO mice had normal histology of the cochlea and retained good hearing at 7 weeks of age. However, at 17 weeks of age, the hearing thresholds of the IDS-KO mice were elevated and exudates were found in the middle ear. The hearing thresholds of the enzyme-treated IDS-KO (IDS-ERT) mice were similar to the wild-type (WT) mice at 17 weeks. Moreover, the microstructure of the inner ear was similar to the IDS-KO by transmission electron microscopy. The histology findings indicated that the microstructure of the inner ear was similar in comparisons between IDS-KO and IDS-ERT mice, even after 10 weeks of treatment. However, the hearing deficits in the MPS II mouse model can be prevented if ERT is started before the onset of hearing impairment. © 2012 Wiley Periodicals, Inc.