To investigate the determinants of the glomerular filtration of proteins in insulin-dependent diabetic patients we studied the fractional clearance of albumin (θAlb) and IgG (θIgG) and the selectivity index (SI = IgG clearance/Alb clearance) in 32 subjects with macroproteinuria (albustix positive), in 29 subjects with microproteinuria (albustix negative), and in 24 healthy control subjects. Fractional clearances of both albumin and IgG were higher in macroproteinuric than in microproteinuric patients, with both groups having higher values than controls (all P < 0.001). In microproteinuric patients with albumin excretion rate (AER) not exceeding 60 μg/min, there was a highly significant correlation between the clearance of albumin and that of IgG. The SI was normal for AERs up to 30 μg/min, but above that albumin filtration increased disproportionately and SI progressively fell. In insulin-dependent diabetics with macroproteinuria, there was a negative correlation between SI and glomerular filtration rate (GFR) (r = −0.68; P < 0.001); the lower SI (0.133 ± 0.06) at higher GFRs also was due to a preferential increase in albumin clearance. Selectivity was progressively lost as GFR declined, and the SI returned to normal values when GFR fell below 10 ml/min/1.73 m2; this was due to a progressively higher rise in the fractional clearance of IgG relative to albumin. We suggest that glomerular filtration of proteins is governed by different determinants at different stages of the disease. In microproteinurics with AER below 60 μg/min, increased intraglomerular pressure seems primarily responsible for the higher proportional filtration of both albumin and IgG. A charge selectivity defect accounts for the proteinuria of microproteinuric diabetics with AERs above 60 μg/min and for that of macroproteinuric diabetics with unreduced GFR since albumin, a polyanion, is preferentially filtered. Pore size selectivity loss is added to the depletion of membrane polyanions in the proteinuria of late nephropathy because the filtration of IgG, a larger but neutral protein, increases relatively more than that of albumin.