Rationale: Interactions of nontypeable Haemophilus influenzae (NTHI) with macrophages are implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the immunologic mechanisms that mediate NTHI-macrophage inflammation are poorly understood. Outer membrane protein (OMP) P6 and lipooligosaccharide (LOS) of NTHI are potent immunomodulators. We theorized that alveolar macrophages in COPD possess fundamental immune defects that permit NTHI to evade host responses. Objective: To test this hypothesis, we obtained human alveolar and blood macrophages from: 1) ex-smokers with COPD, 2) ex-smokers without COPD and 3) nonsmokers. Methods: Alveolar and blood macrophages of each donor were incubated with purified LOS and OMP P6, as well as OMP P2 and the total outer membrane (OM) preparation (0.1-1ug/ml). Measurements: Supernatants (24 hours) were assayed for IL-1, TNF-, IL-10, IL-12 and IL-8 by multianalyte multiplexed flow cytometry. Results: Comparative induction of COPD and nonCOPD alveolar macrophages by LOS and OMP P6 revealed diminished IL-8, TNF- and IL-1 responses of COPD alveolar macrophages (p0.03 for each). COPD alveolar macrophages also had diminished responses to total OMs (p0.03 for each). In contrast, COPD blood macrophages had no significant differences among donor groups in IL-8, TNF- or IL-1 responsiveness to NTHI antigens. Diminished IL-12 responses of COPD blood macrophages to NTHI antigens, compared with nonsmokers, could not be independently dissociated from group differences in age and pack-years. Conclusions: These findings support a paradigm of defective immune responsiveness of alveolar macrophages, but not blood macrophages, in COPD.