Despite a number of studies on biomarkers in chronic obstructive pulmonary disease (COPD), only a few disease-related markers have been identified, yet we still have no satisfactory markers specific to innate immune system and neutrophil activation, which is essential in airway inflammation in COPD. Recent biological studies indicated that lipocalins (LCNs) might be involved in airway inflammation and innate immunity; however, results from available studies on the association of LCNs with COPD are not consistent. We carried out a multicenter prospective observational cohort study to investigate the differences in serum levels of LCN1 and LCN2 between subjects with COPD (n=58) and healthy controls (n=29). Several validated inflammatory markers, including C-reactive protein, tumor necrosis factor-α, interleukin-6, and interleukin-8, were measured. The correlation of LCN1 and LCN2 with clinical features such as smoking habits, lung function, symptoms, and disease category was also analyzed. When comparing with healthy controls, serum levels of LCN1 (66.35±20.26 ng/mL versus 41.16±24.19 ng/mL, P<0.001) and LCN2 (11.29±3.92 ng/mL versus 6.09±5.13 ng/mL, P<0.001) were both elevated in subjects with COPD after adjusting for age, sex, smoking habits, and inflammatory biomarkers. Smoking history and tobacco exposure, as quantified by pack-year, had no impact on systemic expressions of LCN1 and LCN2 in our study. Blood levels of LCN1 and LCN2, respectively, were negatively correlated to COPD Assessment Test and Modified Medical British Research Council score (P<0.001). Disease category by Global Initiative for Chronic Obstructive Lung Disease grade 1–4 or group A–D was not associated with levels of LCNs. Patient-reported exacerbations and body mass index were also tested, but no relationship with LCNs was found. In summary, serum concentrations of LCN1 and LCN2 were both elevated in patients with COPD, with their levels correlating to COPD Assessment Test and Modified Medical British Research Council score. These findings warrant large-scale and longitudinal studies to validate LCNs as circulating biomarkers for COPD.