Copeptin is released from the posterior pituitary gland into systemic circulation in response to various stimuli, including stress. We aimed to evaluate the role of copeptin in determining the severity of the disease in patients with COVID-19. The study was conducted prospectively in two centers between June 1, 2022, and October 1, 2022. Severe and mild-moderate COVID-19 patients were compared in terms of clinical, laboratory and imaging findings, and serum copeptin levels at hospitalization. A total of 90 patients were included in the study; 45 patients were in severe disease groups. Dyspnea, loss of appetite, and loss of smell were significantly more common in the severe disease group (p<0.001, p=0.025, and p<0.001, respectively). Among the tomography findings, the consolidation frequency was similar in both groups (p=0.259). C-reactive protein (CRP), D-dimer, ferritin, lactate dehydrogenase (LDH), procalcitonin, troponin and copeptin levels were higher in the severe group (p<0.05); hemoglobin, total protein and vitamin D levels were lower (p=0.05). The area under the curve (AUC) values for severe disease were 0.643 for copeptin (p=0.019), 0.656 for CRP (p=0.011), 0.684 for procalcitonin (p=0.004), 0.657 for ferritin (p=0.01), 0.72 for D-dimer (p=0), 0.688 for troponin (p=0.002), and 0.672 for age (p=0.005). In our study, copeptin was identified as a new prognostic biomarker indicating the severity of the disease in patients with COVID-19.