β2-microglobulin (β2m), the light chain of major histocompatibility complex class 1 (MHC I), has been identified as a pro-aging factors and involved in the pathogenesis of neurodegenerative disorders by driving cognitive and regenerative impairments. However, little attention has focused on the effect of β2m in development of lung emphysema. Here, we found that concentrations of β2m in plasma were significantly elevated in patients with lung emphysema than those in normal control subjects (1.89 ± 0.12 mg/l vs 1.42 ± 0.06 mg/l, P < 0.01). Moreover, the expression of β2m was significantly higher in lung tissue of emphysema (39.90 ± 1.97% vs 23.94 ± 2.11%, P < 0.01). Immunofluorescence showed that β2m mainly expressed in pro-surfactant protein C positive (pro-SPC+) alveolar epithelial cells and CD14+ macrophages. Exposure of recombinant human β2m and cigarette smoke extract (CSE) in vitro enhanced cellular senescence and inhibited proliferation of A549 cells, which was partially reversed by the presence of anti-β2m antibody. However, anti-β2m antibody didn't attenuate the elevated production of IL-1β, IL-6 and TNF-α in A549 cells exposed to CSE. Immunofluorescence showed that co-localization of β2m and hemochromatosis gene (HFE) protein was observed on A549 cells. These data suggests β2m might participate in development of lung emphysema through inducing lung epithelial cells senescence and proliferation inhibition.