Biomarkers for the progression of lung function in COPD are currently scarce. Plasma fetuin-B (FETUB) was identified by iTRAQ-based proteomics and was verified by ELISA in another group. Information regarding acute exacerbation (AE) was collected in a one-year follow-up programme. FETUB concentrations (1652 ± 427 ng/ml) were greater in COPD patients than in controls (1237 ± 77 ng/ml). The concentrations of FETUB in GOLD II (1762 ± 427 ng/ml), III (1650 ± 375 ng/ml) and IV (1800 ± 451 ng/ml) groups were greater than those in the controls (1257 ± 414 ng/ml) and the GOLD I (1345 ± 391 ng/ml) group. ROCs indicated that FETUB distinguished COPD patients from controls (AUC 0.747, 95% CI: 0.642–0.834) and also GOLD II, III and IV from GOLD I COPD patients (AUC: 0.770, 95% CI: 0.634–0.874). The combination of FETUB and fibrinogen performed better (AUC: 0.804, 95% CI: 0.705–0.881). FETUB also predicted the occurrence of AE (AUC: 0.707, 95% CI: 0.566–0.824) or frequent AE (AUC: 0.727, 95% CI: 0.587–0.840). FETUB concentrations were negatively correlated with FEV1%pred (r = −0.446, p = 0.000) and positively correlated with RV%pred (r = 0.317, p = 0.004), RV/TLC% (r = 0.360, p = 0.004), CT emphysema% (r = 0.322, p = 0.008) and grades of lung function (r = 0.437, p = 0.000). In conclusion, FETUB is likely to assist the diagnosis and management of COPD as a complement for other markers.