Background: Diabetic erectile dysfunction (DMED) is mainly attributed to oxidative stress, and Nrf2 plays an important role in cellular antioxidation and regulates NO production in the vascular endothelium. Probucol maintains endothelial function through its antioxidant activity. This study investigated the efficacy and mechanism of probucol in improving erectile function in streptozotocin-induced diabetic rats. Methods: In our study, thirty 12-week-old Sprague-Dawley male rats were fasted for 12 h. All rats received a 1-time injection of intraperitoneal streptozotocin(60 mg/kg) or vehicle. After 72 h, STZ-treated rats (with random blood glucose concentrations consistently greater than 16.7 mmol/L) were considered diabetic. The diabetic rats were randomly assigned into 2 groups and treated with daily gavage feedings of probucol at doses of 0 and 500 mg/kg for 12 weeks. A positive control group underwent intraperitoneal injection of normal saline followed by daily gavage of saline solution. Erectile function was assessed by electrical stimulation of the cavernous nerves with real-time intracavernous pressure measurement. After euthanasia, penile tissue was investigated using immunohistochemistry, Western blot, and ELISA to assess the proteins of Nrf2/HO-1/DDAH/PPAR-gamma/eNOS pathways. Results: After treatment, the rats in the probucol group presented significantly improved erectile function (P < 0.05) than that of the diabetic group without probucol treatment (DM). Also, protein expression of Nrf2, DDAH, PPAR-gamma, HO-1 and eNOS was significantly higher than that of the DM group (p<0.05). CGMP concentrations and SOD concentrations of probucol-treated rats were higher than those of DM group (P<0.05). The MDA levels and ADMA levels were significantly lower than those of DM group rats (p<0.05). Conclusion: Probucol can improve erectile function via activation of Nrf2, which coordinates the HO-1/DDAH/PPAR-gamma/eNOS pathways in streptozotocin-induced diabetic rats. (C) 2018 Elsevier Inc. All rights reserved.