Background: Among various mechanisms involved in the pathogenesis of diabetic nephropathy (DN), abnormalities in renal nitric oxide (NO) generation has attracted a lot of attention. Tadalafil, a competitive inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 commonly used in the treatment of erectile dysfunction was suggested to play a potential prophylactic role for DN. However, this role has not been fully elucidated. The present study was designed to explore the potential beneficial effect of low- dose tadalafil on the progression of diabetic nephropathy in streptozotocin (STZ) induced diabetic rat model. Methods: After injection of STZ and verifying establishment of diabetes, rats were divided into 4 groups: control, diabetic-control, tadalafil-treated non-diabetic, and tadalafil-treated diabetic groups. Biochemical and hemodynamic parameters affecting the renal function such as blood glucose level, serum level of urea and creatinine, renal blood flow, urine volume, urinary albumin excretion, Na+ and K+ excretion, renal level of nitrite and nitrate, plus renal tissues antioxidant parameters (total antioxidant capacity, superoxide dismutase activity and glutathione content) were detected 8 weeks after administration of tadalafil. Histopathological and electron microscopy examination were performed. Results: Our results demonstrated that tadalafil attenuated the glycemic, renal biochemical, microscopic and ultramicroscopic changes/injuries caused by STZ- induced diabetes. Tadalafil could effectively increase renal blood flow and ameliorate glomerular basement membrane thickening. Conclusions: From the results it can be concluded that tadalafil protects rats against streptozotocin-induced DN possibly, in part, through its effect on renal nitric oxide level and its antioxidant activity.