This paper is the first of its kind to study the impact of Fabry disease (FD) in affected males, and shows that FD is associated with a significant decline in several domains. Using the medical outcomes study (MOS) SF-36 and a FD-specific questionnaire, we compared the observations found among these patients with that obtained for the general US population and other chronic disease states, including Gaucher disease (GD) (another lysosomal storage disorder), end-stage renal disease, stoke and AIDS. Patients with FD have a score profile most similar to patients with AIDS. In comparison with patients with GD, Fabry patients score substantially lower across all domains. Using simple linear regression, potential predictors of health-related quality of life (HRQOL) for Fabry patients were also determined. As in the general population, stroke, cardiac problems and renal disease lead to substantial decrement in HRQOL. In addition, two disease specific symptoms (acroparesthesia and anhidrosis) and pain are also predictors of decreased quality of life. Currently, no specific therapy for FD exists. As enzyme therapy for FD becomes increasingly available, it will be interesting to evaluate the therapy's impact on the quality of life of patients.