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Background: The purpose of this study was to develop a model of ventricular fibrillation arrest with reliable outcomes and minimally invasive methods to study the use of perfluorocarbon emulsions (PFC) as agents to prevent ischemia-reperfusion injury after cardiac arrest as quantified by known biomarkers. Methods: Female Yorkshire swine underwent anesthesia and minimally invasive instrumentation for monitoring under ultrasound. Cardiac arrest was induced with spinal needle insertion at the apex and right parasternal space. Ventricular fibrillation was reliably obtained in all animals on initial attempts. A three-minute circulatory arrest state was observed. Administration of PFC was concurrent with resuscitation including closed chest compressions, epinephrine, amiodarone, and defibrillation at 1J/kg. Primary endpoint was induction of cardiac arrest and tolerance of PFC with return of spontaneous circulation. Blood levels of glial fibrillary acidic protein (GFAP) and ubiquitin C-Terminal Hydrolase-L1 (UCLH1) were secondary end points for three animals. Results: Six of six animals were induced into ventricular fibrillation on initial attempt and two of three survival experiments were able to obtain spontaneous circulation. PFC with pretreatment was tolerated well and no signs of increased pulmonary pressures. GFAP, UCHL1 were significantly lower in intervention animals compared to controls. Conclusions: The results obtained from this preliminary study and technical refinements via additional donated animals have allowed us to make modifications in the choice of PFC, vascular access, and anticoagulation plan. This model provides a consistent method for inducing ventricular fibrillation with minimally invasive techniques. The PFC tested was well tolerated. More robust evaluation of PFC as resuscitative agents is needed with appropriately powered studies.