Hyperplastic glomerular epithelial lesion is an important determinant of the progression of idiopathic focal segmental glomerulosclerosis (FGS). The proliferation and differentiation of glomerular epithelial cells and parietal epithelial cells (PECs) are regulated differently by cyclin and cyclin-dependent kinase inhibitors (CKIs) during nephrogenesis. To access the cellular mechanism underlying epithelial hyperplasia in the development of FGS, the present study applied immunohistochemistry to 21 cases of FGS to demonstrate expression of cell-cycle molecules and phenotypic characterization in proliferative epithelial lesions in FGS. The materials included segmental sclerosis (18.1%), which was divided into monolayer epithelial lesions (64.6%) and cellular lesions (35.4%). All of the cellular lesions expressed cytokeratin, frequently with Ki-67 (82.4%) and less frequently with cyclin A (17.7%), but were invariably negative for podocyte markers (PHM-5 and synaptopodin) and CKIs (p27kip1 and p57kip2). Podocytes in nonsclerotic tuft in the same glomeruli with cellular lesions strongly expressed CKIs and podocyte markers. Moreover, electron microscopy showed that some large proliferating cells with prominent nucleoli have a broad cell base attached to Bowman's capsule. These cells have cilia and a junctional complex with neighboring hyperplastic cells, some of which directly cover the glomerular basement membrane. This suggests that cellular lesions are of PEC origin. Monolayer epithelial lesions also exclusively exhibited a PEC phenotype with reciprocal expression of podocyte markers and cytokeratin. In addition, CKIs are weakly expressed in monolayer epithelial lesions, suggesting a re-entry of cell-cycle quiescent. In conclusion, proliferation of PEC, sustained by repression of CKIs in nature and simultaneous activation of cyclin A, is the actual molecular background to the cellular lesions in FGS. Cellular lesions may result in monolayer epithelial lesions that retain the PEC phenotype and enter a common pathway to glomerulosclerosis.