RATIONALE A disintegrin and metalloproteinase-8 (ADAM8) is expressed by leukocytes and epithelial cells in health, but its contribution to the pathogenesis of COPD is unknown. OBJECTIVES ADAM8 levels were measured in lung, sputum, plasma, and/or bronchoalveolar lavage fluid (BALF) samples from COPD patients, smokers, and non-smokers, and wild-type (WT) mice exposed to cigarette smoke (CS) versus air. COPD-like lung pathologies were compared in CS-exposed WT versus Adam8-/- mice. RESULTS ADAM8 expression was reduced in macrophages, and alveolar and bronchial epithelial cells in the lungs of COPD patients versus controls, and CS- versus air-exposed WT mice. ADAM8 levels were similar in plasma, sputum, and BALF samples from COPD patients and controls. CS-exposed Adam8-/- mice had greater airspace enlargement and airway mucus cell metaplasia than WT mice, but similar small airway fibrosis. CS-exposed Adam8-/- mice had higher lung macrophage counts, oxidative stress levels, and alveolar septal cell death rates, but lower alveolar septal cell proliferation rates and soluble EGF receptor BALF levels than WT mice. Adam8 deficiency increased lung inflammation by reducing CS-induced activation of the intrinsic apoptosis pathway in macrophages. Human ADAM8 proteolytically shed the EGF receptor from bronchial epithelial cells to reduce mucin expression in vitro. Adam8 bone marrow chimera studies revealed that Adam8 deficiency in leukocytes and lung parenchymal cells contributed to the exaggerated COPD-like disease in Adam8-/- mice. CONCLUSIONS Adam8 deficiency increases CS-induced lung inflammation, emphysema, and airway mucus cell metaplasia. Strategies that increase or prolong ADAM8's expression in the lung may have therapeutic efficacy in COPD.