Abstract Background Vasopressin administration has been tested in cardiac arrest. However it has not been tested when cardiac arrest occurs in certain circumstances, as in sepsis, where it may have a major role. The aim of the study was to investigate survival after cardiac arrest in a septic porcine model compared with healthy animals and to explore the effectiveness of adding vasopressin vs epinephrine alone administration. Methods Thirty five healthy piglets of both genders were studied. The piglets were randomly assigned into three groups: group A (n = 8), group B (n = 14), group C (n = 13). Animals of groups B and C were given endotoxin to mimic a septic state before arrest. We applied the same resuscitation protocol to all pigs but we replaced the first dose of epinephrine with vasopressin in pigs of group C. Following surgical preparation and 30 min resting period, baseline measurements were recorded. In order to assess tissue oxygenation, we implemented Near Infrared Spectroscopy (NIRS) with the vascular occlusion technique (VOT) in thirteen lipopolysaccharide (LPS)-treated animals, occluding abdominal aorta and inferior vena cava. Afterwards, LPS (100 μg/kg) was infused in a 30 min period to animals of groups B and C and normal saline to group A. New NIRS measurements were obtained again. Subsequently, we provoked ventricular fibrillation (VF). After 3 min of untreated VF, open chest cardiopulmonary resuscitation (CPR) was performed manually. Primary end point was the restoration of spontaneous circulation (ROSC). Results The chance of ROSC for the groups A, B and C was 75%, 35.7%, and 30.7% respectively. A significant difference in ROSC was established between septic (group B + C) and non septic piglets (group A) (P = 0.046). Vasopressin administration had no effect in outcome. LPS administration decreased oxygen consumption rate, as assessed by NIRS, in peripheral tissues (22.6 ± 7.2. vs 18.5 ± 7.2, P = 0.07). Conclusion Septic piglets have fewer chances to survive after cardiac arrest. No difference in outcome was observed when the first dose of epinephrine was replaced with vasopressin to treat cardiac arrest in the LPS-treated animals.