Rationale: Several studies report that high-density lipoproteins (HDL) can carry alpha1-antitrypsin (AAT, an elastase inhibitor). Objectives: We aimed at determining whether injection of exogenous HDL, enriched or not in AAT, may have protective effects against pulmonary emphysema. Methods: After tracheal instillation of saline or elastase, mice were randomly treated intravenously with saline, human plasma HDL (75mg ApoA1/kg), HDL-AAT (75mg ApoA1-3.75mgAAT/kg) or AAT alone (3.75mg/kg) at 2, 24, 48 and 72h. Results: We have shown that HDL-AAT reached the lung and prevented the development of pulmonary emphysema by 59.3% at 3 weeks (alveoli mean chord length µm: 22.9±2.8 vs 30.7±4.5 μm, p<0.001) whereas injection of HDL or AAT alone only showed a moderate, non-significant protective effect (28.2±4.2 vs 30.7±5μm, p=0.23; and 27.3±5.66 vs 30.71±4.96 μm, p=0.18, respectively). Indeed, protection by HDL-AAT was significantly higher than that observed with HDL or AAT (p=0.006 and p=0.048, respectively). This protective effect was associated (at 6, 24 and 72 hours) with 1) a reduction in neutrophil and macrophage number in the bronchoalveolar lavage fluid (BALF), 2) decreased concentrations of interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α) in both BALF and plasma, 3) a reduction in matrix metalloproteinase (MMP)-2 and MMP-9 activities, and 4) a reduction in the degradation of fibronectin, a marker of tissue damage. Also, HDL-AAT reduced acute cigarette smoke-induced inflammatory response. Conclusions: i.v. HDL-AAT treatment afforded a better protection against elastase-induced pulmonary emphysema than AAT alone, and may represent a significant development for the management of emphysema associated with AAT deficiency.