The aim of this study was to describe the nature and prevalence of hearing loss in Fabry disease (McKusick 301500), a rare X-linked lysosomal storage disorder, and its response to enzyme replacement therapy with agalsidase alfa. Fifteen hemizygous male Fabry patients (aged 25-49 years) were randomized to receive placebo or enzyme replacement therapy for 6 months; all have received open-label enzyme replacement therapy for an additional 24 months thus far. Pure-tone audiometry, impedance audiometry and otoacoustic emission testing were performed at 0 (baseline), 6, 18 and 30 months. Four patients (27%) had bilateral and 7 (47%) had unilateral high-frequency sensorineural hearing loss (SNHL). Two (13%) had unilateral middle ear effusions with conductive losses persisting beyond 6 months. Only 3 (20%) had normal hearing. High-frequency SNHL deteriorated over the first 6 months in both placebo and active treatment groups by a median 4.3 dB ( p =0.002, Wilcoxon matched pairs). This hearing loss subsequently improved above baseline by 2.1 dB at 18 months ( p =0.02) and by 4.9 dB at 30 months ( p =0.004). In conclusion, significant hearing loss, usually high-frequency SNHL, is a common manifestation of Fabry disease in adults. alpha-Galactosidase A replacement therapy with agalsidase alfa appears to reverse the hearing deterioration in these patients. This improvement is gradual, however, suggesting the need for long-term enzyme replacement therapy.