To evaluate long-term effect of sustained proteinuria induced by a single injection of adriamycin (ADR) on occurrence of focal segmental glomerulosclerosis (FSG), we treated 50 Sprague-Dawley (SD) rats, weighing 250 g with 5 mg/kg body weight of ADR. After six months of heavy proteinuria, 40% of ADR-treated rats did not develop FSG. In the remaining 60% of animals, a mild FSG was observed associated with the presence of large tubular casts and interstitial inflammation. Glomerulosclerosis was never observed in absence of tubulointerstitial lesions. Nine months after ADR, all rats exhibited FSG with renal insufficiency but the severest changes were restricted to the tubulointerstitial level. Our results indicate that chronic proteinuria induced by ADR is a relatively good model of glomerular sclerosis, however, the cause of glomerular sclerosis is probably different from that operating in other experimental models of FSG. Both sclerotic changes and progression of disease seem to be dependent on formation of tubular casts with consequent interstitial changes. This study raises the question of the relative role of tubulointerstitial changes in the subsequent development of FSG.