Background and objectives: These analyses were designed to characterize renal disease progression in untreated adults with Fabry disease. Design, setting, participants, & measurements: Data from the Fabry Registry for 462 untreated adults (121 men and 341 women) who had at least two estimated GFR (eGFR) values over a span of ≥12 months before starting enzyme replacement therapy were included. Results: Most men (86 of 121, 71%) had more rapid loss of kidney function than the normal adult population (loss of eGFR > -1 ml/min per 1.73 m2 per year), whereas fewer women (133 of 341, 39%) had rapid loss of kidney function. Patients with rapid progression had significantly higher mean averaged urinary protein to urinary creatinine ratios (UP/Cr) than patients with slower progression (1.5 versus 0.2 for men; 1.4 versus 0.5 for women; P < 0.0001). Patients were grouped into quartiles based on averaged UP/Cr; renal function in men declined more rapidly with higher UP/Cr, with the steepest declines observed in men with UP/Cr > 1.5 (mean eGFR slope, -5.6 ml/min per 1.73 m2 per year; n = 30). eGFR slope declined more slowly in women, with the steepest declines observed in women with UP/Cr > 1.2 (mean eGFR slope, -1.3 ml/min per 1.73 m2 per year; n = 85). Regression models of eGFR slope indicated that UP/Cr is the most important indicator of renal disease progression in adult Fabry patients. In women, lower baseline eGFR and age were also associated with renal disease progression. Women who had clinical events had more rapid loss of kidney function. Conclusions: Urinary protein excretion is strongly associated with renal disease progression in men and women with Fabry disease. Copyright © 2010 by the American Society of Nephrology.