Adiponectin circulates as different oligomers and exerts protective functions on energy metabolism and cell proliferation by AdipoR1 and AdipoR2 receptors. Today, the role of adiponectin on lung was not assessed. Here, we demonstrated high adiponectin levels in serum of COPD patients. Being the oligomerization state critical for adiponectin activities, we analyzed the expression of high molecular weight (HMW) adiponectin oligomers observing a specific HMW increase. We also investigated AdipoRs in COPD lungs demonstrating a AdipoR2 lower specific expression. Next, we investigated in vitro adiponectin effects on lung A549 cells, showing that it decreases viability and increases apoptosis. Then, we examined the effects on A549 cells exposed to TNFα and IL-1ß showing that adiponectin reduces the cytotoxic effects of these pro-inflammatory cytokines. Finally, we demonstrated that adiponectin inhibits NF-κB activation mainly by AdipoR1 and induces the anti-inflammatory IL-10 without modifying IL-6, IL-8, MCP-1 cytokines expression. Thus, our results demonstrate that adiponectin and its receptors represent critical targets to improve diagnostic and therapeutic strategies for lung diseases