Human Tamm-Horsfall glycoprotein, the major urinary protein, is a glycosyl-phosphatidyl-inositol (GPI) - anchored membrane protein which mainly resides at the luminal face of cells of the thick ascending limb of Henle's loop (TAL) and early distal convoluted tubules of nephron. Tamm-Horsfall protein contains exclusively N-linked glycans, mainly of polyantennary type largely sialylated and fucosylated, but also high-mannose glycans. Only a portion of the Tamm-Horsfall protein is released as soluble protein by the action of proteases and in a minor amount by a cell-associated GPI-specific phospholipase. The physiological function of Tamm-Horsfall glycoprotein has not been clarified to date. Since the urinary Tamm-Horsfall protein has a high gel-forming tendency, it has been postulated that it takes part in the water impermeability of TAL. It is also proposed that the Tamm-Horsfall protein plays a protective role towards pyelonephritogenic pathogens such as Escherichia coli. The Tamm-Horsfall protein may inhibit the colonization of these pathogens in the renal mucosa in that the soluble form competes with that exposed at the plasma membrane. Recently, urinary Tamm-Horsfall protein has been implicated in tubulointerstitial nephritis.