Wen-pi-tang is a Chinese prescription used traditionally as a medicine to treat moderate renal failure. In this study, we used rats subjected to subtotal nephrectomy and streptozotocin injection to examine the effects of wen-pi-tang on diabetic nephropathy. Wen-pi-tang was administered at a dose of 50, 100 or 200 mg/kg body weight/day for 15 weeks. Diabetic nephropathy is one of the most serious chronic complications of diabetes mellitus, and renal dysfunction is reflected by proteinuria, decreased creatinine clearance (Ccr) and increased serum urea nitrogen and creatinine (Cr) levels. Wen-pi-tang treatment for 15 weeks resulted in significant reductions of blood glucose and serum urea nitrogen levels, while proteinuria, Ccr and serum Cr levels did not change significantly. Wen-pi-tang also lowered serum triglyceride and thiobarbituric acid-reactive substance levels in a dose-dependent manner. Furthermore, the disorders of the glucose-dependent metabolic pathway due to this pathological condition were normalized by the administration of wen-pi-tang through decreased formation of advanced glycation end-products in the kidney. Wen-pi-tang protected against the development of renal lesions, glomerular sclerosis and mesangial matrix expansion, assessed by histopathological evaluation and scoring. This study suggests that wen-pi-tang treatment could be beneficial in reducing the risk of developing diabetic nephropathy.