COPD is a complex disease with heterogeneous manifestations. Attempts have been made to define different phenotypes that could guide toward better disease understanding. We described before that smokers can develop either panlobular (PLE) or centrilobular emphysema (CLE). The latter has worse small airways remodeling and narrowing, which account for the airflow obstruction similar to asthma. Because of the small airways involvement in CLE similar to asthma, we hypothesized a role for mast cells in CLE but not in PLE. Hence, we investigated mast cell infiltration, along with overall inflammation, and their relation with hyperreactivity and emphysema type in COPD. We studied lung function, emphysema type, mast cells, and overall inflammation in small airways and alveolar walls, along with alveolar wall thickening in 67 subjects undergoing lung resection (59 smokers, 8 nonsmokers). Twenty-seven smokers had CLE, 24 had PLE, and 8 had no emphysema. Mast cells were significantly increased in CLE compared with PLE and control subjects. Especially relevant was the mast cell increase in airway smooth muscle in CLE, which related significantly to airway hyperreactivity. CD4(+)T cells, neutrophils, and macrophages, but not eosinophils and CD8(+)T cells, were significantly higher in CLE than PLE. Alveolar wall thickness was increased in all smokers, but significantly more in CLE. The pathological phenotypes of COPD CLE and PLE show important differences in their overall inflammation with a protagonism of mast cells, which are related to airway reactivity. These findings highlight the distinctness of these COPD phenotypes and the role of mast cells in the pathophysiology of COPD.