OBJECTIVE To conduct a study using a rodent model of chronic intermittent hypoxia (CIH) to define whether endoplasmic reticulum stress (ERS) is involved in the CIH-induced apoptosis of penile tissue and erectile dysfunction (ED), and whether treatment with N-acetylcysteine (NAC) alleviates pathological variations in corpus cavernosa. Previous work has prompted that CIH acted as the major trigger linking obstructive sleep apnea syndrome and ED. MATERIALS AND METHODS Five-month-old Sprague-Dawley male rats were subjected to 8 hours of intermittent hypoxia per day, with or without NAC for 5 weeks. Erectile function, apoptosis of penile tissue, levels of ERS-associated proapoptotic effectors, and nitric oxide (NO) and nitric oxide synthase (NOS) activity were determined. RESULTS Treatment with NAC inhibited apoptosis of penile tissue, the expressions of ERS-related products: BIP, CHOP, caspase12, and Bax, NO, and endothelial NOS. Administration of NAC before CIH significantly improved the CIH-induced impaired erectile function. CONCLUSION Our results show that pre-CIH NAC administration ameliorates the ED following CIH partly by alleviating CIH-induced ERS and cell apoptosis via regulating the expressions of BIP, CHOP, caspase12, and Bax. (C) 2015 Elsevier Inc.