This study investigates the lung microbiome in "healthy" smokers and patients with chronic obstructive pulmonary disease (COPD) using pyrosequencing of 16S rRNA amplicons. Bronchoalveolar lavage (BAL) and surgical lung tissue samples were analyzed to compare bacterial communities in three groups: healthy smokers (HS), never-smokers (NS), and COPD patients (CS). Bacterial 16S sequences were detected in all subjects, with no significant quantitative differences between groups. Taxonomic and non-taxonomic analyses revealed heterogeneity in bacterial communities among HS, similar to those in NS and mild COPD patients. However, moderate and severe COPD patients showed limited bacterial diversity, observed in 28% of healthy subjects. Both approaches showed extensive overlap in bacterial communities among the three groups, with no genera common within a group but unique across groups. The data suggest the presence of a core pulmonary bacterial microbiome, including Pseudomonas, Streptococcus, Prevotella, Fusobacterium, Haemophilus, Veillonella, and Porphyromonas. Notably, significant micro-anatomic differences in bacterial communities were found within the same lung of advanced COPD patients. These findings highlight global and micro-anatomic changes in bacterial communities in severe COPD patients. The study demonstrates that the lung microbiome is not sterile and that bacterial communities vary significantly between individuals and within the same lung. The results suggest that the lung microbiome plays a role in COPD pathogenesis and progression, and that micro-anatomic differences in the lung may contribute to localized disease. The study also shows that the lung microbiome is an independent microbial habitat, not simply a result of contamination. The findings have implications for understanding the role of the microbiome in lung health and disease.This study investigates the lung microbiome in "healthy" smokers and patients with chronic obstructive pulmonary disease (COPD) using pyrosequencing of 16S rRNA amplicons. Bronchoalveolar lavage (BAL) and surgical lung tissue samples were analyzed to compare bacterial communities in three groups: healthy smokers (HS), never-smokers (NS), and COPD patients (CS). Bacterial 16S sequences were detected in all subjects, with no significant quantitative differences between groups. Taxonomic and non-taxonomic analyses revealed heterogeneity in bacterial communities among HS, similar to those in NS and mild COPD patients. However, moderate and severe COPD patients showed limited bacterial diversity, observed in 28% of healthy subjects. Both approaches showed extensive overlap in bacterial communities among the three groups, with no genera common within a group but unique across groups. The data suggest the presence of a core pulmonary bacterial microbiome, including Pseudomonas, Streptococcus, Prevotella, Fusobacterium, Haemophilus, Veillonella, and Porphyromonas. Notably, significant micro-anatomic differences in bacterial communities were found within the same lung of advanced COPD patients. These findings highlight global and micro-anatomic changes in bacterial communities in severe COPD patients. The study demonstrates that the lung microbiome is not sterile and that bacterial communities vary significantly between individuals and within the same lung. The results suggest that the lung microbiome plays a role in COPD pathogenesis and progression, and that micro-anatomic differences in the lung may contribute to localized disease. The study also shows that the lung microbiome is an independent microbial habitat, not simply a result of contamination. The findings have implications for understanding the role of the microbiome in lung health and disease.