Removal of macromolecules with Mr greater than 10,000 had no discernible effect on the detectable nucleation of calcium oxalate crystals from undiluted human urine, but promoted the deposition of crystalline material and markedly increased the degree of aggregation of the precipitated crystals. Calcium oxalate crystals and crystal aggregates precipitated from ultrafiltered urine were, on average, 68% larger than those deposited from whole urine. These findings suggest that urinary macromolecules play a key role in preventing calcium oxalate kidney stone disease by inhibiting the formation of large crystal aggregates and thereby reducing the probability of particle retention in the kidney tubules.