Chronic obstructive pulmonary disease (COPD) is a major health problem with increasing morbidity and mortality throughout the world. YKL-40 is a chitin-binding glycoprotein consisting of 383 amino acids, with a molecular mass of 40 kDa, and its serum level is elevated in inflammatory diseases. YKL-40 is a newly recognized biomarker of inflammation and has not been thoroughly investigated in COPD. The aim of the study is to investigate the relationship between serum YKL-40 levels and severity of COPD. The study population consisted of 52 patients with COPD with the mean age of 60.2 ± 10.1 years. The serum YKL-40 level increased significantly with increasing age (p = 0.022, r = 0.346). In COPD patients, high serum YKL-40 level is correlated to low forced expiratory volume at 1 second (FEV₁, percent of predicted) (r = −0.277, p = 0.047). Moreover, high serum YKL-40 level is correlated to low arterial oxygen pressure (PaO₂, mmHg) (r = −0.387, p = 0.005). The mean serum YKL-40 level was found as 243.1 ± 129.2 ng/ml in COPD patients with desaturation during 6-minute walk test (6MWT) and this value was higher than the mean serum YKL-40 level (155.8 ± 59.1 ng/ml) of COPD patients without desaturation during 6MWT (p = 0.004). This study demonstrated that high serum YKL-40 levels were correlated to severity of COPD. We propose that circulating YKL-40 levels could be a biomarker for hypoxemia and decline in lung function.