Lungs from 25 smokers and 14 lifelong nonsmokers, all over 40 yr of age, were studied 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). Average bronchiolar diameter was not significantly different in smokers compared to nonsmokers; smokers had an excess of airways < 400 .mu.m in diameter (P < 0.03). Among smokers the severity of small airway disease correlated with the percentage of airways that are < 400 .mu.m in diameter (rs = 0.63) and with the extent of centrilobular emphysema (r [correlation coefficient] = 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 small airway disease or centrilobular emphysema. 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.