A novel approach to estimate the severity of COPD exacerbation and predict its outcome is the use of biomarkers. We assessed circulating levels of copeptin, the precursor of vasopressin, C-reactive protein (CRP), and procalcitonin as potential prognostic parameters for in-hospital and long-term outcomes in patients with acute exacerbation of COPD (AECOPD) requiring hospitalization. Data of 167 patients (mean age, 70 years; mean FEV1, 39.9 ± 16.9 of predicted ± SD) presenting to the emergency department due to AECOPD were analyzed. Patients were evaluated based on clinical, laboratory, and lung function parameters on hospital admission, at 14 days, and at 6 months. Plasma levels of all three biomarkers were elevated during the acute exacerbation (p < 0.001), but levels at 14 days and 6 months were similar (p = not significant). CRP was significantly higher in patients presenting with Anthonisen type I exacerbation (p = 0.003). In contrast to CRP and procalcitonin, copeptin on hospital admission was associated with a prolonged hospital stay (p = 0.002) and long-term clinical failure (p < 0.0001). Only copeptin was predictive for long-term clinical failure independent of age, comorbidity, hypoxemia, and lung functional impairment in multivariate analysis (p = 0.005). The combination of copeptin and previous hospitalization for COPD increased the risk of poor outcome (p < 0.0001). Long-term clinical failure was observed in 11% of cases with copeptin < 40 pmol/L and no history of hospitalization, as compared to 73% of patients with copeptin ≥ 40 pmol/L and a history of hospitalization (p < 0.0001). We suggest copeptin as a prognostic marker for short-term and long-term prognoses in patients with AECOPD requiring hospitalization.