Background: Adaptive immune responses are present in patients with chronic obstructive pulmonary disease (COPD), and it has been postulated these processes could be autoreactive. Objectives: To ascertain if humoral autoimmunity could play a role in COPD pathogenesis. Methods: Circulating IgG autoantibodies were detected by immunofluorescence and immunoprecipitation. Immunohistochemistry and immunofluorescence were used to evaluate intrapulmonary IgG and complement (C3) deposition in human lung explants. Autoantibody pathogenicity was also investigated with an antibody-dependent cell-mediated cytotoxicity (ADCC) assay. Measurements and Main Results: The prevalence of anti-HEp-2 epithelial cell autoantibodies in 47 smokers/former smokers with COPD (GOLD Stages 1-4) was greater than among eight subjects with a smoking history but normal spirometry, and 21 healthy, Never-Smoke Controls (68% vs. 13% vs. 10%, respectively, p<0.0001). Antibodies against primary pulmonary epithelial cells were found in 12/12 COPD vs. 3/12 Never-Smoke Controls (p<0.001). Self-antigens immunoprecipitated from 34/35 (97%) of COPD plasmas (vs. 0/12 Never-Smoke Controls). Antibodies against a particular 130 kDa autoantigen (n=7) were associated with decreased body mass index (23.2±2.1 vs. 29.5±1.0 kg/M², p=0.007). Intrapulmonary immune complexes were present in 6/6 and C3 was seen in 5/6 COPD lung explants, unlike 0/6 and 1/6 normals, respectively. Cytotoxicity of pulmonary epithelial cells by allogeneic mononuclear cells also increased 46% after incubation with COPD plasmas (n=10), compared to identical treatments with eight normal specimens (p=0.03). Conclusions: IgG autoantibodies with avidity for pulmonary epithelium, and the potential to mediate cytotoxicity, are prevalent in COPD patients. Autoreactive adaptive immune responses may be important in the etiology of this disease.