We investigated the relationship of renal lesions with the degrees of proteinuria in 57 type 2 diabetic patients with overt proteinuria (urinary protein excretion rate (UP) >> 0.5 g/day). Creatinine clearance (Ccr) ranged from 25.4 to 131.0 ml/min/1.73 m2. Kidney specimens were obtained and the diagnosis of diabetic nephropathy was made in all patients. The degree of each of the following histologic changes were evaluated: diffuse or nodular lesion, the type of nodular change, mesangiolysis, arteriolar hyalinosis and interstitial damage. We divided the patients into the following 4 groups according to Ccr and UP: group A with Ccr >> 60 and UP >> 3 g/day (n = 10), group B with Ccr >> 60 and UP < 3 g/day (n = 10), group C with Ccr < 60 and UP >> 3 g/day (n = 23) and group D with Ccr < 60 and UP < 3 g/day (n = 14), and compared the histologic parameters among the 4 groups. Diffuse index in group A was greater than those in group B (p = 0.05), while those in groups C and D were not different. Nodular index, percentage of patients with nodular lesion did not differ among the 4 groups, however the percentage of glomeruli with complicated nodules (nodular lesion with mesangiolysis and/or microaneurysm) in group C was greater than those in group D (p < 0.05). Hyalinosis index did not differ between group A and B, nor between group C and D, respectively. Interstitial index in group A and B did not differ, however that in group C was greater than in group D (p < 0.05). In addition, the rate of Ccr decrease between renal biopsy and after 12 months was significantly greater in group A and C than in group B and D, respectively (both p < 0.01). These results suggest that 1) mesangial expansion was associated with the degree of proteinuria in patients with slight impaired renal function, 2) tubulointerstitial involvement was associated with the degree of proteinuria in patients with advanced impaired renal function, and 3) these structural changes might be associated with decrease in renal function in diabetic nephropathy.