Exogenous vasopressin is a promising vasopressor when blood pressure is critically threatened, but the role of endogenous vasopressin during cardiopulmonary resuscitation (CPR) is unknown. We assessed the role of endogenous versus exogenous vasopressin in a porcine open chest CPR model. Seven minutes before induction of cardiac arrest, seven pigs received 10/μg/kg of a selective vasopressin V1-receptor-antagonist (Blocked Vasopressin group); another 12 pigs in two groups received saline administration only. After 4 min of untreated ventricular fibrillation followed by 3 min of basic life support CPR, six animals received 0.8 U/kg vasopressin (Exogenous Vasopressin group), whereas the blocked vasopressin group (n = 7), and the remaining six animals received saline placebo only (Endogenous Vasopressin group). Defibrillation was attempted after 14 min of CPR. During basic life support CPR, left ventricular myocardial blood flow was significantly (P < 0.05) decreased in the Blocked Vasopressin group compared with the Exogenous Vasopressin group and Endogenous Vasopressin group (42 ± 5 compared with 64 ± 6 and 66 ± 6 mL · min-1 · 100g-1). Left ventricular myocardial blood flow was significantly decreased in the Blocked Vasopressin group versus Exogenous Vasopressin group versus Endogenous Vasopressin group 90s and 5 min after drug administration, respectively (38 ± 4 and 27 ± 3 vs 145 ± 32 and 110 ± 12 vs 62 ± 4 and 56 ± 6 mL · min-1 · 100g-1,respectively). None of seven Blocked Vasopressin animals, six of six Exogenous Vasopressin pigs, and six of six Endogenous Vasopressin swine had return of spontaneous circulation after 14 min of cardiac arrest including 10 min of CPR (P < 0.05). In conclusion, pigs with blocked endogenous vasopressin had poor coronary perfusion pressure and left ventricular myocardial blood flow during open chest CPR, and could not be successfully resuscitated. All pigs with effective endogenous vasopressin or pigs with effective endogenous vasopressin and additional exogenous vasopressin had good left ventricular myocardial blood flow during experimental CPR, and survived the 1-h postresuscitation phase. We conclude that endogenous vasopressin is an adjunct vasopressor to epinephrine and may serve as a back-up regulator to maintain cardiocirculatory homeostasis.