The neomacrolide antibiotic azithromycin is known to have an anti-inflammatory effect and is increasingly being used in the treatment of chronic inflammatory pulmonary diseases. We investigated whether azithromycin influenced matrix remodeling. Matrix metalloproteinase (MMP)-9 protein levels were measured by ELISA in bronchoalveolar lavaga fluid in 10 stable patients and in 10 lung transplant patients suffering from nCLAD/NRAD. MMP-9 was measured via ELISA before and after 3 to 6months of azithromycin therapy. We further elaborated on the role of MMP-9 by performing gelatin-zymography and gelatinolytic activity assays. Differential and total cell counts on BAL were performed in all cases. The nCLAD/NRAD patients showed higher airway neutrophilia (p<0.0001), ELISA MMP-9 (p<0.0001), zymography proMMP-9 (p<0.0001), activated MMP-9 (p=0.0003) and gelatinolytic activity (p=0.0002) compared to the control group. Airway neutrophilia in the nCLAD/NRAD group significantly decreased after 3-6months of treatment with azithromycin (p=0.0020). This was associated with a decrease in ELISA MMP-9 levels (p=0.0059), in activated MMP-9 shown on zymography (p=0.016) and in gelatinolytic activity (p=0.031). Remarkably, proMMP-9 levels were not altered by azithromycin. Although azithromycin significantly reduced ELISA MMP-9 levels and gelatinolytic activity in transplant patients, these levels remained higher compared to control patients (p=0.0011 and p=0.043). Neutrophil counts, activated MMP-9 and gelatinolytic activity levels in nCLAD/NRAD decreased after azithromycin treatment, but some remained elevated compared to control patients. This illustrates that treatment with azithromycin did not completely restore chronic inflammation in the airways and suggested that preventive therapy may yield added value to curative therapy.