We studied lungs from 25 smokers and 14 lifelong nonsmokers, all over 40 yr of age, to examine the relationship of long-term cigarette smoking to histopathologic changes in the small airways. Despite considerable overlap between the 2 groups, smokers had a significantly higher score (p < 0.01) for small airway disease. The specific morphologic features separating smokers from nonsmokers were increases in goblet cell metaplasia (p < 0.001), smooth muscle hypertrophy (p < 0.05), inflammation in the walls of bronchioles (p < 0.01), and respiratory bronchiolitis (p < 0.001). The average bronchiolar diameter was not significantly different in smokers compared with nonsmokers; however, smokers had an excess of airways less than 400 microns in diameter (p < 0.03). Among smokers, the severity of small airway disease correlated with the percentage of airways that are less than 400 microns in diameter (rs = 0.63) and with the extent of centrilobular emphysema (r = 0.53). Smokers also had an increase in the proportion of bronchial gland mass (p < 0.05), but this pathologic feature was not related to the severity of either small airway disease or centrilobular emphysema. We concluded that prolonged cigarette smoking is associated with progressive pathologic changes in the small airways that may be an important cause of airflow obstruction and that may predispose to the development of centrilobular emphysema.