Objective: The aim of this study is to investigate the correlation between α 2 macroglobulin (A2M) and immune cell infiltration in peripheral blood of patients with chronic obstructive pulmonary disease (COPD). Methods: The GSE38974 dataset was comprehensively analyzed. GO enrichment, KEGG analysis, and GSVA analysis were used to explore potential functions and pathways. CIBERSORT was used to assess tissue infiltrating immune cells. A total of 25 patients with stable COPD and 26 healthy controls were enrolled in this study. The correlation between peripheral blood A2M level and immune cell count was analyzed. ELISA was used to measure the concentration of A2M in plasma. The expression of A2M mRNA in cells and peripheral blood was detected by real-time fluorescence quantitative PCR. The expression of arginase 1 (Arg-1), a surface marker of M2 macrophages, was detected by Western blot. Pearson correlation analysis was used for correlation analysis. ROC curve was used to determine the diagnostic sensitivity and specificity of A2M. Results: Bioinformatics analysis of differentially expressed genes (DEGs) in GSE38974 dataset showed that the expression of A2M was decreased in COPD lung tissue, and was related to immune cell infiltration in COPD lung tissue. RT-qPCR and ELISA results showed that the level of A2M was down-regulated in peripheral blood of COPD patients, and the level of A2M protein in peripheral blood was correlated with lymphocytes and monocytes in COPD patients. ROC curve showed that A2M had a diagnostic value for COPD. Further pathway analysis suggested that A2M might be associated with macrophages and other regulatory immune pathways. Knockdown of A2M in M2 macrophages reduced the expression of Arg-1, a surface marker of M2 macrophages. Conclusions: The expression of A2M in lung tissue and peripheral blood of COPD patients is decreased, which is closely related to the immune cell count and immune cell infiltration in COPD patients. A2M may play an important role in the polarization of macrophages to M2 type.