Background: Asthma likely involves an active injury and repair process, including components such as neutrophils and matrix metalloproteinase 9 (MMP-9). Although MMP-9 is increased in lavage fluid and sputum in patients with asthma, controversy exists as to the role of tissue MMP-9. Objective: The purpose of this study was to determine whether increases in submucosal cellular MMP-9, matrix MMP-9 (subepithelial basement membrane [SBM]), or both would be associated with severe asthma, neutrophilic inflammation, and wound repair. Methods: Immunohistochemical staining and analyses of MMP-9, inflammatory cells, transforming growth factor β, and collagen I were performed in endobronchial biopsy specimens, bronchoalveolar lavage fluid, or both from 38 patients with severe asthma and compared with results in 10 patients with mild asthma, 8 patients with moderate asthma, and 10 healthy control subjects. Results: A significantly greater proportion of patients with severe asthma demonstrated MMP-9 staining of the SBM than control subjects (P = .02). Bronchoalveolar lavage MMP-9 levels were also increased in patients with severe asthma (P = .0004). The numbers of submucosal neutrophils and macrophages, but not eosinophils, were significantly higher in asthmatic individuals with MMP-9 staining of the SBM (P = .004 and P = .01, respectively). However, the presence of SBM MMP-9 was associated with a high correlation between lavage and tissue eosinophils (r = 0.58, P = .009). Although the SBM thickness did not differ between groups, higher numbers of transforming growth factor β-positive cells were seen in subjects with SBM MMP-9 staining. Pulmonary function was significantly lower in those asthmatic subjects with SBM staining. Conclusions: These results suggest that localized tissue MMP-9 might play an important role in wound repair and cell trafficking. (J Allergy Clin Immunol 2003;111:1345-52.)