Objective To explore the predictive value of serum procalcitonin (PCT), D-dimer (D-D) and decoy receptor 3 (DcR3) for prognosis of patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and respiratory failure undergoing non-invasive ventilation (NIV). Methods A total of 95 patients with AECOPD and respiratory failure undergoing basic treatment and NIV in the hospital were retrospectively enrolled between September (n=65) 2017 and February 2021. According to prognosis after treatment, they were divided into a good prognosis group and a poor prognosis group (n=30). The general data of all patients were collected. The influencing factors of prognosis were analyzed by multivariate logistic regression model. The levels of DcR3, PCT and D-D were detected by enzyme-linked immunosorbent assay, colloidal gold colorimetry and immunoturbidimetry. The patients condition was assessed by scores of acute physiology chronic health evaluation scoring system Ⅱ (APACHEⅡ). The partial pressure of arterial oxygen (PaO2) and partial pressure of carbon dioxide (PaCO2) were recorded. And the above indexes between the two groups were compared. The relationship between DcR3, PCT, D-D and APACHEⅡ score, PaO2, PaCO2 was analyzed by Pearson correlation analysis. The prognostic value of DcR3, PCT and D-D was analyzed by receiver operating characteristic (ROC) curve. Results There was no significant difference in gender, GOLD grading or underlying diseases between the poor prognosis group and the good prognosis group (P>0.05), but there were significant differences in age, DcR3, PCT, D-D, APACHEⅡ score, PaO2 and PaCO2 after treatment (P<0.05). DcR3, PCT, D-D, APACHEⅡ score and PaCO2 in the poor prognosis group were higher than those in the good prognosis group, while PaO2 was lower than that in the good prognosis group (P<0.05). Logistic regression analysis showed that DcR3 ≥5.50 ng/mL (OR=21.889), PCT ≥ 5.00 μg/L (OR=3.782), D-D ≥3.00 μg/L (OR=4.162) and APACHEⅡ score ≥20 points (OR=2.540) were all influencing factors of prognosis (P<0.05). The results of Pearson correlation analysis showed that DcR3, PCT and D-D were positively correlated with APACHEⅡ score and PaCO2, while negatively correlated with PaO2 (P<0.05). The results of ROC curve analysis showed that area under ROC curve of DcR3, PCT and D-D for predicting the prognosis were 0.745 (95%CI 0.631 - 0.859), 0.691 (95%CI 0.579 - 0.803) and 0.796 (95%CI 0.696 - 0.895), respectively (P<0.05). Conclusion The serum DcR3, PCT and D-D levels are related to disease progression in patients with AECOPD and respiratory failure after NIV, which have good predictive efficiency for prognosis and can be applied as important biological indexes to evaluate prognosis and guide treatment.