Bronchiectasis (BE) and chronic obstructive pulmonary disease (COPD) share similar clinical characteristics and are frequently co-diagnosed (BE-COPD). BE-COPD is associated with worse outcomes, but the mechanisms of this are unknown. Therefore, the present study aimed to investigate differences in the lung microbiome between patients with BE and those with the overlap of BE and COPD, known as BE-COPD. The study included 281 patients from a UK center, with 176 having BE and 105 having BE-COPD. Proteobacteria were the most prevalent phyla, with Haemophilus and Streptococcus being the dominant genera. Alpha diversity was significantly lower in the BE-COPD group, as indicated by SWDI (p=0.02), CI (p=0.04), and SI (p=0.03). However, the two groups had no significant differences in beta diversity. Random Forest analysis identified reduced levels of commensal taxa in the BE-COPD group, including Neisseria, Prevotella, Campylobacter, and Fusobacterium. Validation in the EMBARC-BRDGE cohort from the UK, Italy, and Spain (208 patients) confirmed reduced alpha diversity (SWDI p=0.06, CI p=0.02, SI p=0.03) and significant changes in beta-diversity (PERMANOVA p=0.02) in the BE-COPD group. Random Forest analysis also revealed a depletion of Neisseria, Prevotella, Campylobacter, and Fusobacterium in the BE-COPD arm. In conclusion, this study demonstrates that BE-COPD is associated with reduced microbial diversity and depletion of anti-inflammatory commensal taxa in two large cohorts.