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Abstract: Background: Fabry disease is characterized by accumulation of glycosphingolipids, such as globotriaosylceramide (Gb3), in many tissues and body fluids. A novel plasma biomarker, globotriaosylsphingosine (lyso-Gb3), is increased in patients with the disease. Until now, lyso-Gb3 was not detectable in urine, possibly because of the presence of interfering compounds. Methods: We undertook to: 1) characterize lyso-Gb3 in urine; 2) develop a method to quantitate urinary lyso-Gb3 by mass spectrometry; 3) evaluate urinary lyso-Gb3 as a potential biomarker for Fabry disease; and 4) determine whether lyso-Gb3 is an inhibitor of α-galactosidase A activity. We analyzed urinary lyso-Gb3 from 83 Fabry patients and 77 healthy age-matched controls. Results: The intraday and interday bias and precision of the method were <15%. Increases in lyso-Gb3/creatinine correlated with the concentrations of Gb3 (r 2 =0.43), type of mutations (p =0.0006), gender (p <0.0001) and enzyme replacement therapy status (p =0.0012). Urine from healthy controls contained no detectable lyso-Gb3. Lyso-Gb3 did not inhibit GLA activity in dried blood spots. Increased urinary excretion of lyso-Gb3 of Fabry patients correlated well with a number of indicators of disease severity. Conclusion: Lyso-Gb3 is a reliable independent biomarker for clinically important characteristics of Fabry disease. [ABSTRACT FROM AUTHOR]