Rationale: Defective efferocytosis (phagocytic clearance of apoptotic cells) in the airway may perpetuate inflammation via secondary necrosis in COPD. We have previously reported that low-dose azithromycin improved alveolar macrophage (AM) phagocytic function in vitro. Objectives: We investigated collectins (Mannose binding lectin (MBL), and surfactant protein D (SP-D)) and mannose receptor (MR) in COPD and their possible role in the azithromycin-mediated improvement in phagocytosis. Methods: 1) In vitro effects of azithromycin on AM expression of MR were investigated. 2) MBL, SP-D and MR were measured in COPD subjects and controls. 3) Azithromycin (250mg orally daily for five days then 2x weekly (total 12 weeks)) was administered to 11 COPD subjects. Assessments included AM phagocytic ability and expression of MR, MBL, SP-D, bronchial epithelial cell apoptosis, pulmonary function, CRP, blood/BAL leucocyte counts, cytokine production and T-cell markers of activation and phenotype. Results: Azithomycin (500ng/ml) increased MR expression by 50% in vitro. AM MR expression and levels of MBL and SP-D were significantly reduced in COPD subjects vs controls. In COPD patients following azithromycin therapy, we observed significantly improved AM phagocytic ability (pre: 9.9% vs post: 15.1%), reduced bronchial epithelial cell apoptosis (pre: 30.0% vs post: 19.7%) increased MR and reduced inflammatory markers in the peripheral blood. These findings implicate the MR in both the defective phagocytic function of AM in COPD and as a target for the azithromycin-mediated improvement in phagocytic ability. Our findings indicate a novel approach to supplement existing therapies in COPD.