Current concepts of the pathogenesis of emphysema suggest that it results from an imbalance of elastase and antielastase activity within the alveolar structures. Although emphysema that is associated with hereditary deficiency of serum α₁-antitrypsin conforms to this scheme, the major risk factor in the more common form of emphysema is cigarette smoking. A study was designed to evaluate the premise that cigarette smoking may be associated with an acquired, functional defect in lung α₁-antitrypsin. Determination of the antielastase activity of α₁-antitrypsin obtained from the lungs of smoking and nonsmoking individuals revealed a nearly twofold reduction in the functional activity of this elastase inhibitor in the lungs of cigarette smokers. These data suggest that cigarette smokers may lose some of the normal antielastase protective screen of the lower respiratory tract, making them more vulnerable to destructive lung disease.