Cigarette smoke is the primary cause of chronic obstructive pulmonary disease (COPD). COPD is a characterised by chronic inflammation, progressive lung function decline and emphysematous changes in lung. However, the underlying mechanisms and immune responses that underpin COPD are incompletely understood. Here we demonstrate the role of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in mediating the pathogenesis of COPD. In wild-type (WT) mice, cigarette smoke exposure increased TRAIL protein in lung homogenates and serum. Cigarette smoke increased TRAIL+ inflammatory cells, namely CD11b+ inflammatory monocytes in the lung. Immunohistochemistry confirmed that these parenchyma-associated inflammatory monocytes were the major source of TRAIL in cigarette smoke exposed WT mice. TRAIL-deficient (TRAIL-/-) mice had reduced cigarette smoke-induced lung inflammation, associated with reduced influx of inflammatory CD11b+ monocytes, myeloid dendritic cells and γδT cells into the lung. Moreover, mRNA expression of inflammatory cytokines (TNF-α, Saa3 and MMP12) and chemokines (CCL-2, -3, -7, -12 and -20) were reduced in TRAIL-/- mice. Surprisingly, TRAIL-/- mice developed spontaneous airway remodelling, characterised by increased airway epithelial cell thickness and numbers, and collagen deposition. These were further increased in TRAIL-/- mice by cigarette smoke exposure. TRAIL-/- mice exposed to cigarette smoke had improved lung function and reduced emphysema-like alveolar enlargement. Consistent with the alveolar enlargement, cigarette smoke-induced apoptosis in lungs was significantly reduced in TRAIL-/- mice. Our study is the first to show that TRAIL plays an important role in the pathogenesis of COPD and provides further evidence for TRAIL being a pivotal inflammatory cytokine in respiratory diseases.