Background <p>COPD is heterogeneous, with immunosuppression contributing to immune dysfunction. We hypothesized that the immunosuppressive response varies by inflammatory phenotype during both stable disease (SCOPD) and acute exacerbations (AECOPD).</p> Methods <p>COPD patients were monitored during AECOPD hospitalization and subsequent clinical stability. Serum key pro- and anti-inflammatory molecules were measured. Circulating Th17 and regulatory T (Treg) cells, early-myeloid-derived suppressor cells (e-MDSC), monocytic-MDSC (M-MDSC), and plasmacytoid dendritic cells (pDCs) were analyzed by flow cytometry. Sputum was tested for viruses and bacteria. Eosinophilic inflammation was defined by a blood eosinophil count of ≥ 2%.</p> Results <p>The study included 78 COPD patients and 17 controls. 49% of patients consistently had a non-eosinophilic (Non-Eos) phenotype, and 18% an eosinophilic (Eos) phenotype across both AECOPD and SCOPD. Interestingly, 28% of patients exhibited Non-Eos-AECOPD followed by eosinophilia in SCOPD, while 5% showed the opposite. Immunosuppressive cell frequency increased in both Eos-AECOPD and Non-Eos-AECOPD. While Tregs increases were comparable, the M-MDSC increase in Non-Eos-AECOPD was 1.6 times greater than in Eos-AECOPD. During the stable phase, the Eos phenotype associated with more Tregs and fewer M-MDSCs. Cytokine levels rose significantly during Non-Eos-AECOPD but not in Eos-AECOPD. Critically, within the Non-Eos-AECOPD group, those who later developed eosinophilia in SCOPD showed the most pronounced increases in M-MDSC frequency and cytokine levels.</p> Conclusions <p>Immunosuppressive cell distribution in SCOPD and triggered immunosuppression pathways during AECOPD are dependent on the inflammatory profile. Understanding the COPD inflammatory phenotype might help predict immune responses and lead to more targeted treatments.</p> Trial registration <p>Not applicable.</p>