Measurements of differential renal protein clearance (ratio of the renal clearance of immunoglobulin-G to that of transferrin) have been performed in long-standing diabetics with varying amounts of proteinuria. In seventy-one diabetics the IgC-transferrin clearance ratio (0.44 ± 0.04, mean ± S.E.M.) was significantly lower than in seventeen normal subjects (1.85 ± 0.24). The mean IgG-transferrin clearance ratio was significantly lower in fourteen of these diabetics with normal amounts of proteinuria than in normal subjects. A further decrease in clearance ratio was apparent when nonproteinuric (125 mg./24 hr.) and minimally proteinuric (500 mg./24 hr.) diabetics were compared. Deterioration of renal function in proteinuric diabetics was associated with an increase in the IgG-transferrin clearance ratio. The results taken overall suggest that an initial fall and a delayed rise in the clearance ratio occurs in individuals who progress to terminal renal failure. The initial fall in the IgG-transferrin clearance ratio may reflect the earliest renal changes of diabetic nephropathy. The relationship of this fall to the onset of carbohydrate intolerance remains to be clarified.