IgG1 and IgG4 have similar molecular weights but differ in pH (about 9 and 4.6, respectively). Their different rates of excretion in the urine of diabetic patients may indicate an impairment of charge selectivity in the kidney filter. Working on this hypothesis, a sensitive new ELISA for the detection of urinary IgG4 has been developed. This method can detect less than 1 ng/ml of this immunoglobulin; total IgG was detected by a RIA method developed by our laboratory. Twenty-eight Type I diabetic patients with or without clinical nephropathy were included in a cross-sectional study. An additional seven diabetic patients were followed over time, and eight diabetic pregnant women were studied during the different trimesters of pregnancy. Whereas both IgG4 and total IgG values were increased in clinically nephropathic patients, levels of IgG4, but not IgG1-3, were enhanced in patients without clinical nephropathy. In the latter group as well, IgG4-positive patients were microalbuminuric; all but one of the remaining patients were IgG4 and albumin negative. There was no significant variation in IgG4 values with time on repeated samples. The increased glomerular filtration rate in diabetic pregnancy did not significantly modify the levels of IgG4 in the urine. These results are in accordance with a selective excretion of this medium to large sized anionic protein (IgG4) in incipient (or stage III) diabetic nephropathy. Urinary IgG4 could be an additional useful marker when studying diabetic patients with early and pre-clinical stages of diabetic nephropathy.