Thrombomodulin (TM) and its molecular species have been identified as markers of vascular endothelial cells (EC). In the present study, using high-performance liquid chromatography (HPLC) in 7 normal subjects, 5 chronic glomerulonephritis (GN) patients, and 25 diabetes mellitus (DM) patients, the TM molecular species separated from plasma showed seven heterogeneous fragments of 94, 74, 48, 36, 27, 14, and 12 kDa. Comparing the diabetic patients and healthy subjects, it was found that plasma TM generally, and its 74-kDa molecular species particularly, were increased in diabetic patients and the increase became more apparent as the disease progressed in severity. Comparing the patients with diabetic nephropathy and those with nephritis of the same degree of renal dysfunction, both groups had increased levels of TM, but the distribution of the molecular species differed; that is, the 74-kDa form increased in the diabetic patients and the 12-kDa species increased markedly in the nephritis patients. Glycation of the various TM molecular species increased more in the diabetic patients than in healthy subjects. There was a significantly positive correlation between the HbA(1c) and the 74-kDa TM molecular species in diabetic patients. These findings suggest that a fluctuation in the blood glucose level is significantly related to vascular EC damage in DM.