Perfusion of rat kidneys with polycations (protamine sulfate, poly-L-lysine), resulted in glomerular epithelial alterations very similar to those observed in proteinuric states, particularly rat aminonucleoside nephrosis. Such changes did not occur after exposure to neutral or anionic macromolecules (poly-DL-alanine, myoglobin, heparin, poly-L-glutamic acid and ovalbumin). Morphigenetic factors in the polycation-induced lesion included retraction and flattening of foot processes, narrowing of filtration slits, formation of occluding junctions between foot processes and cell swelling. The associated suppression of histochemically demonstrable glomerular polyanion suggested that neutralization of cell surface anionic sites was an important factor in the causation of the lesion, which was reversible by reperfusion with heparin. Observations by freeze-fracture confirmed the similarity of the polycation-induced lesion to the epithelial changes in rat aminonucleoside nephrosis. Following exposure to polycations there was also "staining" of anionic sites on epithelial and endothelial cell membranes and glomerular basement membrane. Reperfusion of protamine-treated kidneys with heparin resulted in restoration of previously suppressed colloidal iron staining and the formation of spherical, electron-dense (heparin-protamine) complexes within the glomerular filter.