The airways of COPD patients are often colonized with bacteria leading to increased airway inflammation. This study sought to determine whether systemic cytokine responses to microbial pathogen-associated molecular patterns (PAMPs) are increased among subjects with severe COPD. In an observational cross-sectional study of COPD subjects, PAMP-induced cytokine responses were measured in whole blood ex vivo. We used PAMPs derived from microbial products recognized by toll-like receptors 1, 2, 4, 5, 6, 7, and 8. Patterns of cytokine response to PAMPs were assessed using hierarchical clustering. One-sided Student's t-tests were used to compare PAMP-induced cytokine levels in blood from patients with and without severe COPD, and for subjects with and without chronic bronchitis. Of 28 male patients, 12 had moderate COPD (FEV1 50%-80%) and 16 severe COPD (FEV1 <50%); 27 participants provided data on self-reported chronic bronchitis, of which 15 endorsed chronic bronchitis symptoms and 12 did not. Cytokine responses to PAMPs in severe COPD were generally lower than in subjects with milder COPD. This finding was particularly strong for PAMP-induced interleukin (IL)-10, granulocyte colony stimulating factor, and IL-1β. Subjects with chronic bronchitis showed higher PAMP-induced IL-1RA responses to most of the PAMPs evaluated. COPD patients with more severe disease demonstrated a diminished cytokine response to PAMPs, suggesting that chronic colonization with bacteria may dampen the systemic innate immune response.