To characterize the defect in glomerular permselectivity responsible for proteinuria after renal transplantation, we studied 10 patients with moderate proteinuria (median 0.37 g/d, range 0.20-0.79), 16 patients with the nephrotic syndrome (6.73 g/d, 3.9-14.6), 8 living related donor transplant recipients without any history of rejection (median proteinuria 0.26 g/d, 0.06-0.58), and 12 healthy volunteers. The fractional clearance of neutral dextrans > 54 A was significantly higher in nephrotic patients, demonstrating a defect in glomerular size selectivity. Using a log-normal model of glomerular pore size distribution, r*(5%) and r*(1%), indices for the presence of large pores, were increased in the nephrotic patients. The fractional clearance of negatively charged dextran sulfate was significantly higher in all patient groups, indicating a loss of glomerular charge selectivity. Biopsy findings showed more prominent glomerular lesions in the nephrotic group compared with the moderately proteinuric group. We conclude that mild proteinuria late after renal transplantation is associated with a defect in glomerular charge selectivity. The development of nephrotic range proteinuria is associated also with a defect of glomerular size selectivity, which correlates with prominent glomerular pathology.