Background: It is known that pro-inflammatory cytokines suppress in vitro the gene expression and protein production of erythropoietin (Epo). We hypothesized that systemic inflammation in patients with chronic obstructive pulmonary disease (COPD) may influence Epo production, particularly during episodes of exacerbation of the disease (ECOPD) where an inflammatory burst is known to occur. Objectives: We compared the plasma levels of Epo and high-sensitivity (hs) C-reactive protein (hsC-RP) in patients hospitalized because of ECOPD (n = 26; FEV1: 48 ± 15% predicted), patients with clinically stable COPD (n = 31; FEV1: 49 ± 17% predicted), smokers with normal lung function (n = 9), and healthy never smokers (n = 9). Methods: Venous blood samples were taken between 9 and 10 a.m. after an overnight fast into tubes with EDTA (10 ml) or without EDTA (10 ml). Plasma levels of Epo (R&D Systems Inc., Minneapolis, Minn., USA) and hsC-RP (BioSource, Belgium) were determined by ELISA. Results: Log-Epo plasma levels were significantly lower (0.46 ± 0.32 mU/ml) in ECOPD than in stable COPD (1.05 ± 0.23 mU/ml), smokers (0.95 ± 0.11 mU/ml) and never smokers with normal lung function (0.92 ± 0.19 mU/ml) (p < 0.01, each). In a subset of 8 COPD patients who could be studied both during ECOPD and clinical stability, log-Epo increased from 0.49 ± 0.42 mU/ml during ECOPD to 0.97 ± 0.19 mU/ml during stability (p < 0.01). In patients with COPD log-Epo was significantly related to hsC-RP (r = –0.55, p < 0.0001) and circulating neutrophils (r = –0.48, p < 0.0001). Conclusions: These results show that the plasma levels of Epo are reduced during ECOPD likely in relation to a burst of systemic inflammation.