Matrix metalloproteinase-9 (MMP-9) has been consistently identified in the lungs of patients with COPD. However, its role in the development of the disease remains undefined. Mice that specifically express human MMP-9 in their macrophages were generated and morphometric, biochemical and histological analyses were conducted on the transgenic and littermate control mice over one year in order to determine the impact of macrophage MMP-9 expression on emphysema formation and lung matrix content. Lung morphometry was normal in transgenic mice at two months of age (mean linear intercept=50±3 littermate mice vs. 51±2 transgenic mice). However, after twelve months of age the MMP-9 transgenic mice developed significant airspace enlargement (mean linear intercept=53±3 littermate mice vs. 61±2 MMP-9 transgenic mice; p<0.04). Lung hydroxyproline content was not significantly different between wild-type and transgenic mice but MMP-9 did significantly decrease alveolar wall elastin at one year of age (4.9±0.3% area of alveolar wall in the littermate mice vs. 3.3±0.3% area of alveolar wall in the MMP-9 mice; p<0.004). Thus, these results establish a central role for MMP-9 in the pathogenesis of this disease by demonstrating that expression of this protease in macrophages can alter the extracellular matrix and induce progressive airspace enlargement in mice.