Endoplasmic reticulum stress (ERS)-induced apoptosis of airway epithelial cells plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Furthermore, autophagy is closely related to ERS under apoptosis. Here, this study aimed to investigate the role of the reciprocal interaction between autophagy and ERS in the cigarette smoke extract (CSE)-induced apoptosis of human bronchial epithelial (HBE) cells. Cell apoptosis was detected by flow cytometry analysis. Protein expression was examined by Western blot. The mRNA expression was detected using real-time quantitative reverse transcription PCR (qRT-PCR). The results showed that CSE treatment induced apoptosis, autophagy, and expression of ERS-related proteins in HBE cells. Furthermore, autophagy inhibition by 3-MA significantly decreased protein expression of GRP78, p-PERK, and p-eIF2α and increased CHOP, ATF4, and caspase-4, whereas ERS inhibition by 4-PBA led to autophagy suppression. Moreover, the CSE-induced autophagy was diminished by knockdown of GRP78, PERK, or eIF2α but enhanced by knockdown of ATF4 or CHOP; however, the CSE-induced HBE apoptosis was enhanced by knockdown of GRP78, PERK, or eIF2α but was attenuated by knockdown of ATF4 or CHOP. Additionally, both sodium hydrosulfide (NaHS) and melatonin attenuated the CSE-induced apoptosis, enhanced the CSE-induced autophagy, increased GRP78, p-PERK, and p-eIF2α, and decreased CHOP, ATF4, and caspase-4, via SIRT1/ORP150 pathway. Collectively, this study provided evidence about the role of the reciprocal interaction between autophagy and ERS in CSE-induced apoptosis of HBE cells. © 2018 IUBMB Life, 71(1):66-80, 2019.