Background and Aims. Autoimmune processes are involved in the progression of chronic obstructive pulmonary disease (COPD). Autoantibodies against cytokeratin 18 (CK18) and cytokeratin 19 (CK19) could be associated with lung injury. We undertook this study to investigate the role of these autoantibodies against CK18 and CK19 in the development of COPD. Methods and Results. We used blood samples from 228 COPD patients or 136 healthy controls and male C57BL/6j mice as experimental subjects to analyze the serum autoantibody levels against CK18 or CK19 autoantigen by enzyme-linked immunosorbent assay (ELISA). We found that the circulating autoantibody levels of IgG, IgA, IgM against CK18 and CK19 were elevated in patients with COPD compared with healthy controls, which were increased gradually as the severity of the disease increases, especially in GOLD III and GOLD IV with the exception of anti-CK19 IgG and anti-CK18 IgA auto antibodies. Moreover, we observed that the serum levels of anti-CK18 and anti-CK19 IgG autoantibodies were higher in mice exposed to cigarette smoke compared with mice exposed to room air for 6 months and 9 months. Additionally, we identified the distribution of antibodies and the presence of autoantibodies (IgG) against CK18 and CK19 in the damaged lung tissues of mice. Conclusions. Increased circulating autoantibodies against CK18 and CK19 are closely related to the progression of COPD, which play an important role in the process of lung injury in COPD, suggesting that it is promising for anti-CK18 and anti-CK19 autoantibodies to serve as a tool to monitor lung damage and guide treatment. (C) 2017 IMSS. Published by Elsevier Inc.