Chronic obstructive pulmonary disease (COPD) is characterized by periodic exacerbations, some of which are caused by nontypeable Haemophilus influenzae (NTHI). P6 is an outer membrane lipoprotein that is highly conserved among strains of NTHI. We hypothesized that lymphocytes from patients with COPD who have exacerbations due to NTHI have a decreased ability to recognize P6. The in vitro lymphocyte proliferative response to P6 in 36 patients with COPD and 12 healthy control subjects was studied. Ten patients who had exacerbations due to NTHI in the previous 12 months showed statistically significant lower proliferation to P6 (stimulation index, log transformed mean +/- standard error 0.82 +/- 0.17) compared with 26 patients who had no exacerbations due to NTHI in the previous 12 months (1.42 +/- 0.13) and to 12 healthy control subjects (1.61 +/- 0.16). These three groups had no significant difference in the lymphocyte proliferative response to tetanus toxoid. There was no difference in serum antibody levels to P6 in the two groups with COPD. These results indicate that decreased proliferation of T cells to P6 is associated with exacerbations of COPD and suggest that the ability of T cells to recognize P6 is associated with relative protection from exacerbations due to NTHI.