Airway remodelling is a critical feature of chronic obstructive pulmonary disease (COPD, aka emphysema). It narrows the airways and impairs lung function. Alteration of the extracellular matrix (ECM) proteins is a major characteristic of remodelling in COPD. Fibulin-1 is a glycoprotein that stabilises ECM and binds to fibronectin, periostin and tenacin-C. Two fibulin-1 variants (c and d) occur in mice and predominate in humans. The levels of fibulin-1, especially fibulin-1c, are increased in the lung tissue of COPD patients. However, the role of fibluin-1 in the COPD pathogenesis is unclear. We found that airway remodelling defined by increased collagen and a-smooth muscle actin (aSMA) around small airways and total collagen levels in lung tissue occurred after 8-weeks of cigarette smoke (CS)-exposure in our mouse model of experimental COPD. Moreover, fibulin-1 levels were increased around the small airways in lung tissue. CS-exposed fibulin-1c-deficient (-/-) mice were protected from airway remodelling, and had reduced collagen and aSMA around the airways compared to wild-type mice. They were also protected from emphysema and impaired lung function. Levels of periostin were increased and fibroenctin and tenascin-C were decreased in the lung. Surprisingly, CS-exposed fibulin-1c-/- mice also had less inflammatory cells and cytokines/chemokines (CXCL1, IL-33 and TNF-a) in the airways and lung. Our data suggest that fibulin-1c could regulate airway remodelling, emphysema and lung function changes through alterations in the deposition of ECM. Fibulin-1c also plays a key role in regulating inflammatory responses in experimental COPD. Thus, fibulin-1c may be a therapeutic target in COPD.