The pathogenesis of focal glomerular sclerosis (FGS) and its relation to proteinuria and idiopathic nephrotic syndrome are unknown. Urine protein excretion in Sprague-Dawley rats increased with age. Fifty per cent of 12-month and 90 per cent of 24-month-old animals were proteinuric (greater than 20 mg. per day). Heavily proteinuric old rats manifested biochemical changes characteristic of nephrotic syndrome without significant loss of renal function. Three-month, 6-month, and nonproteinuric 12-month-old animals had mesangial deposits of IgM in occasional lobules of some glomeruli and slight mesangial hyperplasia. Four proteinuric 12-month-old rats had diffuse 4+ deposits of IgM in the mesangium of most glomeruli, basement membrane thickening and epithelial cell foot process fusion without FGS. The mesangial IgM deposits eluted in acid buffer and did not fix complement. Six proteinuric 12-month-old rats had focal and segmental areas of glomerular sclerosis with adhesions to Bowman's capsule, foamy cells, intraluminal eosinophilic deposits and capillary wall wrinkling and collapse. These lesions were more advanced in 24-month-old animals. Nonproteinuric 24-month-old rats did not have detectable FGS. Mesangial uptake of colloidal carbon was normal in proteinuric and nonproteinuric animals without FGS. Mesangial uptake of colloidal carbon was normal in proteinuric and nonproteinuric animals without FGS and reduced in proteinuric animals with FGS. In the aging rat the development of proteinuria and mesangial IgM deposition apparently precede development of a focal sclerotic glomerular lesion with histologic and ultrastructural features similar to FGS in man. The generalized impairment of mesangial phagocytic function in proteinuric rats with FGS suggests that this lesion may result from mesangial overload and dysfunction consequent to the persistent increase in glomerular permeability and proteinuria.