OBJECTIVES: Fabry disease is a rare, progressive, X-linked lysosomal storage disorder caused by deficiency of α-galactosidase A. Multiple major organs are affected, impacting on health-related quality of life (HRQoL). Symptomatic disease requires lifelong treatment with intravenous enzyme replacement therapy (ERT; two products available), which has been shown to improve long-term outcomes, delay organ damage and improve HRQoL. We present the results of a systematic review of the humanistic burden of Fabry disease. METHODS: We conducted a systematic search of MEDLINE, Embase and congress proceedings to identify studies reporting general HRQoL in patients with Fabry disease.  RESULTS: The search identified 30 relevant publications reporting data for ERT-treated and -untreated male and female adult and paediatric patients. The majority of studies assessed HRQoL using the 36-item Short-Form Health Survey (SF-36; n=18) and/or 5-dimension European Quality of Life instrument (EQ-5D; n=8). HRQoL was reduced compared with the general population (n=12), and was worse than or similar to other chronic or progressive conditions (n=8); furthermore, HRQoL deteriorated with age (n=2) and with progressive disease severity (n=1). Two clinical trials were identified (one placebo-controlled and one open-label) that described HRQoL improvements with ERT (agalsidase alfa). There were five analyses of registry data for patients receiving ERT: four studies demonstrated sustained HRQoL improvements with up to 5 years of agalsidase alfa treatment, and one study reported improvements after 1 and 2 years of agalsidase beta therapy. In two small cohorts, overall HRQoL either improved in all SF-36 domains after 10 years of ERT (n=6 patients) or did not significantly decrease over 7 years of ERT (n=10 patients). CONCLUSIONS: Patients with Fabry disease experience significant impairment in HRQoL, and the limited available data suggest that this improved while on ERT. Further studies are required to quantify treatment-associated HRQoL outcomes.