An abnormal increase in proteolytic enzymes is thought to play a key role in pulmonary emphysema. Alveolar macrophage proteolytic enzymes include cathepsin L, cathepsin S, matrix metalloproteinase 1, 9, and 12, and a number of studies have implicated these proteinases in the alveolar destruction that characterizes emphysema. The aim of this study was to investigate cathepsin L, cathepsin S, matrix metalloproteinase 1, 9, and 12 mRNA expression in alveolar macrophages isolated from patients with varying degrees of emphysema and to correlate their level of expression with measures of emphysema. Alveolar macrophages were isolated from fifty-four patients who underwent surgical resection for lung carcinoma. The level of mRNA expression was determined using real-time PCR. Emphysema was quantified using high-resolution CT scans. Alveolar macrophages were also cultured for 24 h and 48 h; the effect of proinflammatory mediators and promoter polymorphisms on expression was analyzed. There was a significant correlation between matrix metalloproteinase 1 mRNA expression and emphysema. A higher level of matrix metalloproteinase 1 mRNA was associated with more severe emphysema. Matrix metalloproteinase 12 mRNA expression was increased in current smokers as compared with former smokers. Furthermore, there was a negative correlation between matrix metalloproteinase 12 gene expression and carbon monoxide diffusing capacity. The matrix metalloproteinase 9 C-1562T polymorphism significantly influenced matrix metalloproteinase 9 mRNA expression in alveolar macrophages. These results suggest that alveolar macrophage matrix metalloproteinase 1 and 12 may have a role in the lung structural changes leading to the development of emphysema. Furthermore, these data provide evidence to support the concept that multiple proteinases, causing both elastin and collagen degradation, are important in the pathogenesis of pulmonary emphysema.