Spontaneously developing focal and segmental glomerulosclerosis (FGS) in Buffalo/Mna rats was studied. There were no differences in the occurrence of the disease between male and female rats. Plasma macromolecules were detected in the urine samples of 2-month-old rats using sodium dodecyl sulphate polyacrylamide gel electrophoresis. All 4-month-old animals had proteinuria in excess of 30 mg/24 h. At the age of 4 months, sclerotic glomeruli were rarely observed. At the age of 6 months, all animals had a few sclerotic glomeruli in every kidney section examined. Animals which were 22 months old had sclerotic lesions in 37.8–52.1% of the glomeruli. Ultrastructural examination revealed that alterations in epithelial cells, such as effacement of foot processes, vacuolization, and a podocytic membrane-like structure, were found at the age of 2 months. The animals examined were neither uremic nor hypertensive. Our present study showed that female as well as male Buffalo/Mna rats had an earlier onset of the disease than the other strains of rats and that alterations in glomerular epithelial cells were first detected in the early stage of the disease.