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Background: Patients with Fabry disease (FD, α-galactosidase A deficiency or absence) accumulate glycosphingolipids, leading to progressive dysfunction of kidneys, heart and nervous system. Generalizable real-world outcomes following agalsidase beta treatment initiation outside trials are limited. We investigated the associations of long-term agalsidase beta treatment with estimated glomerular filtration rate (eGFR) changes over time and the risk of developing a composite clinical event in a matched analysis of treated and untreated patients with FD., Methods: Agalsidase beta-treated adult patients (aged ≥16 years) from the Fabry Registry and adult untreated patients from a natural history cohort were matched 1:1 and X:X (with one occurrence and multiple occurrences of each untreated patient, respectively) by sex, phenotype, age and (for eGFR slope analysis) baseline eGFR. Outcomes included eGFR slope over 5 years and composite clinical event risk (cardiovascular, cerebrovascular or renal event, or death) over 10+ years. As a surrogate indicator of therapeutic response in paediatric patients, the percentage experiencing normalization in plasma globotriaosylceramide (GL-3) from treatment initiation was assessed in patients aged 2 to <16 years., Results: Overall, eGFR slopes for 1:1-matched untreated and treated adult patients [122 pairs (72.1% male)] were -3.19 and -1.47 mL/min/1.73 m 2 /year, respectively (reduction in rate of decline = 53.9%, P  = .007), and for X:X-matched [122 untreated/950 treated (59.4% male)] were -3.29 and -1.56 mL/min/1.73 m 2 /year, respectively (reduction in rate of decline = 52.6%, P  < .001). Agalsidase beta treatment was associated with lower risk of clinical events, with hazard ratios of 0.41 ( P  = .003) and 0.67 ( P  = .008) for 1:1-matched and X:X-matched analyses, respectively. Plasma GL-3 declined markedly in paediatric patients and normalized in most within 6 months of treatment initiation., Conclusion: Agalsidase beta treatment preserves kidney function and delays progression to severe clinical events among adult patients with FD. Plasma GL-3 levels analysed in paediatric patients showed normalization of elevated pre-treatment levels in most patients., Competing Interests: J.L.B., A.H., M.M., S.R., B.G., L.A.R. and E.P. are/were full-time employees of Sanofi and may hold/have held stock and/or stock options in that company. C.W. has received honoraria for board meetings and lecturing from Amicus Therapeutics, Chiesi Pharmaceuticals, Idorsia Pharmaceuticals, Sanofi and Takeda. R.J.D. is a consultant for Sanofi., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)