Based on our previous finding, of increased small airways disease in centrilobular emphysema (CLE) when compared with panlobular emphysema (PLE), we hypothesized that smokers who develop CLE would have increased airway responsiveness associated with airway inflammation and exaggerated airway narrowing, but not smokers with PLE. We compared preoperative methacholine challenge with the morphologic and cellular inflammatory characteristics of the airways in the lungs of six nonsmokers, 10 smokers with CLE, and five smokers with PLE. The airways of the CLE group were narrower than those of the nonsmokers (KS < 0.05) and the PLE group (KS < 0.05), but perimeters were not different. A greater percentage of airways in the CLE group showed infolding of the epithelium and lumen deformity than in the PLE group and nonsmokers (p < 0.05). Airway inner wall thickening (WI) was increased in the CLE group when compared with the PLE group and nonsmokers (p < 0.05), and WI correlated significantly with PC20 in the CLE group (r = -0.64, p < 0.01) but not in the PLE group and nonsmokers. The number of T lymphocytes in the airway walls correlated with PC20 in the CLE group (r = -0.50, p < 0.05) but not in the PLE group. In conclusion, despite similar age, smoking history, and range of airflow limitation, there was a clear difference in the methacholine responsiveness between the emphysema groups, suggesting that responsiveness is not just a reaction to smoking but either a reaction developing in some smokers or an abnormality initially present in some smokers which, in combination with exposure to cigarettes, determines the development of a type of lung disease: CLE.