Introduction: Early and accurate prediction of survival to hospital discharge following resuscitation after cardiac arrest (CA) is a major challenge. Biomarkers can be used for early and accurate prediction of survival and prognosis following resuscitation after CA, but none of those identified so far are sufficient by themselves. Hypothesis/Problem: The goal of this study was to investigate the predictive power of the serum copeptin level for determining the return of spontaneous circulation (ROSC) and prognosis of patients with non-traumatic out-of-hospital cardiac arrest (OHCA) who underwent cardiopulmonary resuscitation (CPR). Methods: A total of 76 consecutive consenting adult patients who were diagnosed as non-traumatic OHCA and 63 age- and sex-matched healthy controls were enrolled. The patients were divided into two groups based on whether or not they had ROSC. The ROSC group was divided into two sub-groups according to whether death occurred within 24 hours or after 24 hours following ROSC. Serum copeptin, high-sensitivity cardiac troponin (hs-cTnI), creatine kinase-muscle/brain (CK-MB), glucose, and blood gas values were compared between the groups. Results: Serum copeptin levels were significantly higher in the patient group than control group (P <.001). Receiving operator characteristic analysis revealed a cut-off copeptin level of 27.29pmol/L, with 98.7% sensitivity and 100.0% specificity, for distinguishing patients from controls. Serum copeptin levels were significantly lower in the ROSC group than non-ROSC group (P = .018). Additionally, the mean serum hs-cTnI level was significantly higher in the ROSC group than non-ROSC group (P = .032). However, there were no significant differences in the mean serum glucose level and CK-MB levels or arterial blood gas levels between the ROSC and non-ROSC groups (all P >.05). Ten (38.5%) of the patients died within the first 24 hours after ROSC, whereas 16 (61.5%) survived longer than 24 hours. Serum copeptin levels were significantly lower in patients who survived longer than 24 hours compared with those who died within the first 24 hours. Moreover, the mean CPR duration was significantly lower in patients surviving more than 24 hours compared with less than 24 hours. Conclusion: The serum copeptin level may serve as a guide in diagnostic decision making to predict ROSC in patients undergoing CPR and determining the short-term prognosis of patients with ROSC.