While a majority of lung cancer patients have a history of tobacco use, the variation in lung cancer risk among smokers can be 20-fold. One well-documented host factor related to the risk of lung cancer is COPD, including emphysema and chronic bronchitis. COPD shares common etiologic factors with lung cancer, particularly cigarette smoking. Previous studies have suggested that a1-antitrypsin deficiency (A1ATD) not only can cause emphysema but is also associated with an increased risk of multiple malignancies, including lung cancer. Several mechanisms of tumorigenesis have been postulated between A1ATD and lung cancer development, as follows: excess neutrophil elastase, the counterpart of a1-antitryp-sin, may facilitate cancer development by causing tissue damage and air trapping that fosters longer carcinogen exposure; may promote cancer progression by degrading the intercellular matrix barrier; and may lead to cancer development through the tumor necrosis factor signaling pathway. To test the hypothesis that a1-antitrypsin and neutrophil elastase may be critical in the causal pathway from tobacco smoke exposure to lung cancer development, we conducted a case-control study using functionally significant polymorphic markers to assess the role of protease inhibitor-1 (PI1) and neutrophil elastase-2 (ELA2), which encode functional variations of the two proteins in lung cancer risk in concert with known environmental and host factors.