Background: Some COPD patients are more susceptible to exacerbations than others. Mechanisms underlying these differences in susceptibility are not well understood. We hypothesized that altered cell mediated immune responses may underlie a propensity to suffer from frequent exacerbations in COPD. Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from 24 stable COPD patients, eight frequent exacerbators (>= 3 diary-card exacerbations/year) and 16 infrequent exacerbators (< 3 diary-card exacerbations/year). Detailed multi-parameter flow cytometry was used to study differences in innate and adaptive systemic immune function between frequent and infrequently exacerbating COPD patients. Results: The 24 COPD patients had a mean (SD) age of 76.3 (9.4) years and FEV1 1.43 (0.60) L, 53.3 (18.3)% predicted. PBMCs of frequent exacerbators (FE) contained lower frequencies of CD4+ T central memory cells (CD4+ Tcm) compared to infrequent exacerbators (IE) (FE = 18.7 %; IE = 23.9 %; p = 0.035). This observation was also apparent in absolute numbers of CD4+ Tcm cells (FE = 0.17 x 10(Lambda)6/mL; IE = 0.25 x 10(Lambda)6/mL; p = 0.035). PBMCs of FE contained a lower frequency of CD8+ T effector memory cells expressing HLA-DR (Human Leukocyte Antigen - D Related) compared to IE COPD patients (FE = 22.7 %; IE = 31.5 %; p = 0.007). Conclusion: Differences in the adaptive systemic immune system might associate with exacerbation susceptibility in the `frequent exacerbator' COPD phenotype. These differences include fewer CD4+ T central memory cells and CD8+ T effector memory cells.