The development of focal and segmental glomerular hyalinosis and sclerosis (FSGHS) and its relation to mesangial accumulation of macromolecular substances, lipids in particular, were studied in two models of the nephrotic syndrome, induced by puromycin aminonucleoside and adriamycin. Rats with chronic nephrosis induced by multiple subcutaneous injections of puromycin aminonucleoside during 12 weeks showed FSGHS lesions in 7.8% of their glomeruli. Only 0.3% of the glomeruli from rats with chronic nephrosis of 12 weeks' duration induced by one intravenous dose of adriamycin showed FSGHS lesions (p = 0.0012). Body weight curves, proteinuria, and serum levels of total protein, cholesterol, and triglycerides were similar in both groups. The mesangial area in glomeruli of puromycin aminonucleoside-nephrotic rats showed significantly higher amounts of lipid as compared with glomeruli in adriamycin-nephrotic rats, and within FSGHS lesions in particular extensive accumulation of lipid was observed. In addition, increased lipid accumulation within the mesangial area was found in rats with acute (i.e., of 10 days' duration) puromycin aminonucleoside nephrosis as compared with rats with acute adriamycin nephrosis. These differences in lipid accumulation between the two models may reflect differences in mesangial cell injury or, more likely, in function. In puromycin aminonucleoside nephrosis the increased mesangial uptake of tracers is well known. Mesangial function in unilateral adriamycin nephrosis was studied using colloidal carbon as a tracer. No differences in mesangial handling of carbon were observed between adriamycin-perfused, contralateral nonperfused, and saline-perfused control kidneys. In chronic puromycin aminonucleoside nephrosis increased accumulation and incorporation of macromolecular substances, such as lipids in mesangial cells, may lead to overproduction of matrix substance with more trapping of lipids and eventually sclerosis. In adriamycin nephrosis normal mesangial activity and, consequently, low uptake of macromolecules and endogenous lipids may protect the glomerulus against sclerosis, notwithstanding increased serum lipid levels.