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Background: Microbiome residing in the respiratory tract has emerged as an important player in the etiology and progression of COPD, but results are conflicting regarding the features of respiratory tract microbiome in COPD and at exacerbations and it is unknown whether these features differ by ethnicity and geography. Method: To address these questions, we enrolled healthy individuals and patients with COPD, including healthy-COPD pairs from same households, from four geographical regions of Yunan province, representative of different ethnicities and/or environmental exposures. Sputum and oropharyngeal swabs were collected from these healthy individuals and from COPD patients at stable state (COPD) or exacerbations (AECOPD) and subjected to 16S microbiome profiling. Results: Both COPD disease status and region had an impact on alpha-diversity of sputum and oropharyngeal microbiomes, with AECOPD having the lowest microbiome diversity. Shifts in the relative abundance (≥ 1.5 fold, adj. p < 0.05) of microbes at healthy, exacerbation and stable COPD. Microbes enriched at exacerbation COPD were primarily Proteobacteria and Firmicutes phylum in upper respiratory tract. In the lower respiratory tract, population-based study did not find any statistical differential abundance of microbe, however, paired-based study showed phylum of Proteobacteria, Chloroflexi, Bacteroidota, Acidobacteriota, Desulfobacterota, Firmicutes and Verrucomicrobiota enriched in exacerbation COPD. Conclusions: COPD is associated with specific changes in upper and lower respiratory tract microbiomes, whereas exacerbation events confer additional alterations in respiratory tract microbiome compositions. These specific microbiome changes may inform future study on the pathogenesis or management of COPD.