Diabetic nephropathy is a major cause of end-stage renal disease (ESRD) in the general population. It is es-timated that diabetic nephropathy will eventually develop in about 40% of all patients with diabetes; therefore, prevention is critical for delaying the development and progression of diabetic kidney disease. Despite extensive efforts, medical advances are still not successful enough to prevent the progression of the disease. In the present study, we focused on the comparison of combination therapies and whether they offered additional renopro-tection. Type 2 diabetes mellitus was induced by intraperitoneally administering streptozotocin (90 mg/kg) in neonatal rats and then these rats were treated with rosiglitazone (1.0 mg/kg) in combination with glimepiride (0.5 mg/kg) or with pioglitazone (2.5 mg/kg) in combination with glimepiride (0.5 mg/kg). Diabetic nephropathy markers were evaluated by biochemical and ELISA kits and renal structural changes were examined by light mi-croscopy and transmission electron microscopy. Results show that the combination of pioglitazone with glimepir-ide is more effective in amelioration of diabetic nephropathy than rosiglitazone with glimepiride drug therapy due to glycemic control, suppressing albumin excretion rate, total protein excretion rate and augmented TNF-a signal-ing during the development of streptozotocin induced type 2 diabetic nephropathy.