Introduction: The PARAMEDIC2-trial reported a higher survival rate comparing standard epinephrine treatment with placebo, but severe neurologic impairment was found more often in patients who received epinephrine. Angiotensin II (AT2) has been recently authorized by FDA and EMA to treat distributive shock in adults. It is not approved as a vasopressor in the treatment of cardiac arrest (CA) and has not been studied in a standardized model of out-of hospital cardiac arrest with subsequent guideline-based cardiopulmonary resuscitation (CPR) before. Hypothesis: AT2 administration during CPR will 1. result in higher rates for return of spontaneous circulation (ROSC) after modeled out-of-hospital CA and 2. will achieve a greater increase in mean arterial blood pressure (MAP) compared to standard epinephrine bolus regimen. Methods: After legal approval (81-02.04.2019A072) and in conformance with the AHA position statement (Circulation 1985; 71:849A), we conducted a prospective, randomized trial in 25 swine weighing 32 to 43.5 kilogram bodyweight (kgBW) under general anesthesia. In 22 swine randomized to intervention groups i) EPI or ii) AT2, ventricular fibrillation was induced electrically and mechanical ventilation was discontinued. After 10 minutes (min) of untreated CA, ventilation was resumed and CPR was performed adapted to current guidelines for up to 56 min. After the third unsuccessful defibrillation (6 min CPR), swine received either i) boluses of epinephrine 0.01 mg/kgBW every 4 min or ii) an initial bolus of AT2 (25 μg/kgBW) followed by continuous infusion at 1 μg/kgBW/min. Three animals served as sham controls and received identical treatment but neither CA nor CPR. Results: ROSC was achieved in 7/22 swine and in 5/20 requiring vasopressors (EPI 1/10 vs. AT2 4/10, n. s.). The initial vasopressor bolus increased MAP significantly more in AT2 compared to EPI (p = 0.03). However, this could not be maintained under continuous infusion of AT2. Conclusions: For the first time, we have demonstrated the feasibility of successful guideline-based CPR using AT2 as sole vasopressor. But still, questions such as the optimal dosage remain. We strongly encourage larger trials to investigate this newly available drug also for the treatment of CA.