The effect was measured of incubating crystals of calcium oxalate monohydrate (COM) with 10 per cent normal urine and 10 per cent artificial urine on the surface zeta potential (ZP) produced on the crystals by various inhibitors of the agglomeration of COM. These studies showed that natural urine contains some constituent, not present in the artificial urine, which interferes with the ability of the inhibitors tested to produce a highly negative ZP on the crystal surface. A second series of studies showed that there are two factors in urine which modify the effect of the polyanionic inhibitors, Tamm-Horsfall mucoprotein (THM) and high ionic strength. At concentrations greater than 10(-8) mol./l., THM interfered with the binding of other polyanions to the surface of COM and reduced the maximum negativity of the ZP achievable on the crystals. This effect was very marked over the urinary concentration range (5 X 10(-8) to 6 X 10(-7) mol./l.; four to 48 mg./l.). By increasing the ionic strength of the incubation medium over the urinary range, the electrical double layer around the COM crystals was compressed and the interference caused by THM accentuated. Within most of the urinary range of ionic strength, THM interfered with the binding of other polyanions at concentrations greater than 10(-9) mol./l. In highly concentrated urine, at the top end of the urinary range of ionic strength, THM polymerized readily and to such an extent that it overwhelmed the inhibitors in urine and strongly promoted the agglomeration of COM crystals. The polymerization point of THM was found to be inversely related to the ionic strength of the solution in which it was dissolved.