Cigarette smoke (CS) exposure is a major risk factor for COPD. We investigated whether CS-induced DAMP release or DAMP-mediated inflammation contributes to susceptibility for COPD. Samples, including bronchial brushings were collected from young and old individuals, susceptible and non-susceptible for the development of COPD, before and after smoking, and used for gene profiling and airway epithelial cell (AEC) culture. AECs were exposed to CS extract (CSE) or specific DAMPs. BALB/cByJ and DBA/2J mice were intra-nasally exposed to LL-37 and mitochondrial (mt)DAMPs. Functional gene-set enrichment analysis showed that CS significantly increases the airway epithelial gene-expression of DAMPs and DAMP receptors in COPD patients. In cultured AECs, we observed that CSE induces necrosis and DAMP release, with specifically higher galectin-3 release from COPD-derived compared to control-derived cells. Galectin-3, LL-37 and mtDAMPs increased CXCL8 secretion in AECs. LL-37 and mtDAMPs induced neutrophilic airway inflammation, exclusively in mice susceptible for CS-induced airway inflammation. Collectively, we show that in airway epithelium from COPD patients, the CS-induced expression of DAMPs and DAMP receptors in vivo and the release of galectin-3 in vitro is exaggerated. Further, our studies indicate that a predisposition to release DAMPs and subsequent induction of inflammation may contribute to the development of COPD.