Mechanisms responsible for the development of focal segmental sclerotic lesions of the glomerulus (FSGS lesions) in transplanted kidneys were investigated by morphometric analysis. The mean glomerular area and the interstitial area were measured using computerized image analysis to compare implantation biopsies (so-called 1-h biopsies; 1Bx) with later biopsies (episode Bx; EBx) that had been taken for diagnostic purposes to identify the cause of deteriorating renal function. Groups of patients with (group A, n = 15) or without (group B, n = 10) FSGS lesions were compared. Twelve of 15 in group A and all in group B had lost graft function due to chronic allograft nephropathy. It was found that neither the mean glomerular area nor the interstitial area differed significantly between the two groups in either 1Bx or EBx. The interstitial area was significantly increased (P = 0.007) and the mean glomerular area tended to be increased (P = 0.085) in EBx compared with 1Bx in group A but not in group B. The serum creatinine level at the time of EBx in group A correlated with the interstitial area (P = 0.031) but not the mean glomerular area. However, there was no similar correlation in group B. In conclusion, factors for the development of FSGS lesions in transplanted kidneys may be the increase in interstitial area and possible glomerular hypertrophy following transplantation, rather than pre-existing reduced renal mass of the donor kidneys.