We analysed the sequence of structural changes leading to focal segmental glomerulosclerosis (FSGS) in chronic Masugi nephritis. The protocol resulted in an immediate onset of the disease and the development of segmental sclerosis in a considerable proportion of glomeruli within 28 days of serum injection. Throughout the study, the degree of structural damage was significantly correlated with protein excretion. Even 1 day after injection of the serum, the whole spectrum of early lesions was encountered involving all three cell types. Endothelial detachments, mesangiolysis and podocyte foot process effacement were most prominent. There was focal persistence of capillary microthrombosis but, generally, mesangial and endothelial injuries recovered. The development of podocyte lesions was different: on one hand recovery was seen leading to the re-establishment of an interdigitating foot process pattern, and on the other persistent podocyte detachments from peripheral capillaries allowed the attachment of parietal epithelial cells to “naked” portions of the glomerular basement membrane (GBM), and thus to the formation of a tuft adhesion to Bowman's capsule. Progressive podocyte degeneration at the flanks of an adhesion permitted expansion of the adhesion by encroachment of parietal cells onto the tuft along the denuded GBM. Inside an adhesion, capillaries and mesangial areas either collapse or become obstructed by hyalinosis or thrombosis. Resident cells disappear progressively from inside an adhesion; macrophages may invade. Segmental sclerosis in this model consists of collapsed tuft structures adhering broadly to the cortical interstitium. Proliferation of mesangial cells did not contribute to this development. Recovery of endothelial and mesangial lesions was associated with cell proliferation in early stages of the disease; podocyte proliferation was not encountered at any stage. We conclude that the inability to replace an outmatched podocyte crucially underlies the development of sclerosis. Severe podocyte damage cannot be repaired but leads to tuft adhesions to Bowman's capsule followed by progressive collapse of tuft structures inside an adhesion, resulting in segmental glomerulosclerosis.