Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory respiratory disease characterized by airflow obstruction. Protein disulfide-isomerase A3 (PDIA3) is an isomerase enzyme located in endoplasmic reticulum, nucleus, and cell membrane. Although the potential role of PDIA3 was actively studied in various kinds of diseases including neurological disease, cancer, and infection disease, its role in COPD is unclear. In this study, we investigated the expression level of PDIA3 in lung tissues of non-COPD and COPD patients and the role of PDIA3 in lung epithelial cells. We found that the protein level of PDIA3 in lung homogenates from patients with COPD was higher than those from non-COPD donor. The PDIA3 protein level was negatively correlated with the forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and diffusing capacity of the lung for CO (DLCO). Immunohistochemical staining for PDIA3 showed that PDIA3 expression was higher in the lung epithelial cells of COPD patients compared to non-COPD donor, which was confirmed using primary small airway epithelial cells (SAECs). The level of PDIA3 was higher in SAECs isolated from COPD patients than in SAECs from non-COPD donor. Overexpression of PDIA3 significantly enhanced cigarette smoke extracts (CSE)-induced interleukin-8 release in lung epithelial cells. Moreover, CSE induced epithelial cell apoptosis, which was increased by PDIA3 overexpression. Taken together, increased level of PDIA3 might contribute to COPD pathogenesis by enhancing inflammation and apoptosis in lung epithelial cells.