Eighty-four patients with insulin-dependent diabetes mellitus had studies of renal function and quantitative renal morphometry including mesangial volume fraction (Vvmes/glom), index of arteriolar hyalinosis, percentage of globally sclerosed glomeruli (%GS), and interstitial volume fraction for total renal cortex (Vvint/T). There was significant correlation among these four parameters, and all four structural parameters correlated with glomerular filtration rate and the log of urinary albumin excretion. Stepwise multiple regression analysis showed that Vvmes/glom and Vvint/T were additive, suggesting that they are partially independent. Arteriolar hyalinosis and %GS did not improve the correlations further. We hypothesize that Vvmes/glom, Vvint/T, arteriolar hyalinosis, and %GS represent multiple but probably interrelated pathologic mechanisms leading to the functional disturbances of diabetic nephropathy. Longitudinal studies of patients with diabetes and studies of patients with diseases producing interstitial expansion in the absence of glomerular disease may help clarify the independent role of interstitial expansion in the kidney disease of diabetes mellitus.