The hypothesis that damage to the visceral epithelial cell plays a central role in the pathogenesis of focal and segmental glomerulosclerosis was tested by injecting saponin solutions of increasing concentration (0.1, 0.3, 0.6 and 1.0 mg/ml) in Bowman's space of superficial glomeruli in the Munich-Wistar rat. The microinjections were performed both with and without intermittent clamping of the renal vessels during two minutes. After 8 to 14 days the injected glomeruli were examined by light microscopy. The injected glomeruli were classified as, normal (NL), showing visceral epithelial cell damage (VECD), showing focal and segmental glomerulosclerosis (FSGS) or showing global sclerosis (GS). Swelling and intracellular vacuolation of the visceral epithelial cells (VEC) were considered as VECD. FSGS-lesions were seen most frequently in the glomeruli injected with 10 nl of a saponin solution with a concentration higher than 0.3 mg/ml. In view of the light microscopic lesions four glomeruli in a 0 mg/ml, the 0.1 mg/ml and the 0.6 mg/ml saponin groups were examined after 40 minutes with transmission electron microscopy (TEM) to evaluate the selectivity of the lesions. In the 0 and 0.1 mg/ml group only occasional limited fusion of the foot processes of the podocytes was seen. In the 0.6 mg/ml group segmental lysis of the VEC without ultrastructural damage to the capillary basement membrane or the endothelial and mesangial cells was seen. It is concluded that it is possible to induce direct segmental lysis of the visceral epithelial cells in a single glomerulus, and that this damage to the visceral epithelial cells is related to the development of focal and segmental glomerulosclerosis.