Objective To investigate the changes of serum hypoxia-inducing factor 1α (HIF-1α), pulmonary surfactant protein D (SP-D), and Copeptin levels in patients with chronic obstructive pulmonary disease (COPD) complicated with type II respiratory failure, and to analyze their prognostic value. Methods A total of 120 patients with COPD combined with type II respiratory failure admitted to 988 Hospital of Chinese People's Liberation Army Joint Logistic Support Force from January 2020 to January 2023 were selected as the study objects, and were divided into poor prognosis group and good prognosis group according to the survival status within 28 days of treatment. Compare clinical data and serum levels of HIF-1 , SP-D, and Copeptin between two groups. Use receiver operating characteristic curve (ROC) to analyze the predictive value of serum indicators for prognosis. Results After 7 days of treatment, the serum levels of HIF-1α, SP-D, and Copeptin in the poor prognosis group were higher than those in the good prognosis group (P<0.05); the serum levels of HIF-1α, SP-D, and Copeptin were positively correlated with APACHE II score, cTnT, NT proBNP, and CRP (P<0.05); the AUC predicted by HIF-1α+SP-D+Copeptin was higher than that predicted by single index and predicted by any two indexes (P<0.05). Conclusion The increase of serum HIF-1α, SP-D and Copeptin levels is closely related to poor prognosis and severity of COPD patients with type 2 respiratory failure, which has important clinical significance in predicting prognosis.