Background This study was designed to compare the effects of epinephrine with those of vasopressin on vital organ blood flow during closed-chest cardiopulmonary resuscitation (CPR) in a pig model of ventricular fibrillation. Methods and Results Vasopressin was compared with epinephrine by randomly allocating 28 pigs to receive either 0.2 mg/kg epinephrine (n=7), 0.2 U/kg vasopressin (low dose) (n=7), 0.4 U/kg vasopressin (medium dose) (n=7), or 0.8 U/kg vasopressin (high dose) (n=7) after 4 minutes of ventricular fibrillation and 3 minutes of closed-chest CPR. Left ventricular myocardial blood flow, determined by use of radiolabeled microspheres during CPR, before and then 90 seconds and 5 minutes after drug administration was 17+/-2, 43+/-5, and 22+/-3 mL.min(-1).100 g(-1) (mean+/-SEM) in the epinephrine group; 18+/-2, 50+/-6, and 29+/-3 mL.min(-1).100 g(-1) in the low-dose vasopressin group; 17+/-3, 52+/-8, and 52+/-6 mL.min(-1).100 g(-1) in the medium-dose vasopressin group; and 18+/-2, 95+/-9, and 57+/-6 mL.min(-1).100 g(-1) in the high-dose vasopressin group (P<.001 at 90 seconds and 5 minutes between epinephrine and high-dose vasopressin, and P<.01 at 5 minutes between epinephrine and medium-dose vasopressin). At the same times, calculated coronary systolic perfusion pressures were 12+/-2, 36+/-5, and 18+/-2 mm Hg in the epinephrine group; 10+/-1, 39+/-6, and 26+/-5 mm Kg in the low-dose vasopressin group; 11+/-2, 49+/-6, and 38+/-5 mm Hg in the medium-dose vasopressin group; and 10+/-2, 70+/-5, and 47+/-6 mm Hg in the high-dose vasopressin group (P<.01 at 90 seconds and 5 minutes between epinephrine and high-dose vasopressin); and calculated coronary diastolic perfusion pressures were 15+/-2, 24+/-2, and 19+/-2 mm Hg in the epinephrine group; 13+/-1, 25+/-2, and 20+/-1 mm Hg in the low-dose vasopressin group; 13+/-2, 25+/-2, and 21+/-2 mm Hg in the medium-dose vasopressin group; and 13+/-2, 35+/-3, and 24+/-2 mm Hg in the high-dose vasopressin group (P<.05 at 90 seconds between epinephrine and high-dose vasopressin). Total cerebral blood flow was significantly higher after high-dose vasopressin than after epinephrine (P<.05 at 90 seconds and P<.01 at 5 minutes between groups). Five animals in the epinephrine, 5 in the low-dose vasopressin, 7 in the medium-dose vasopressin, and 6 in the high-dose vasopressin groups were successfully resuscitated and survived the 1-hour observation period, Conclusions We conclude that administration of vasopressin leads to a significantly higher coronary perfusion pressure and myocardial blood flow than epinephrine during closed-chest CPR in a pig model of ventricular fibrillation.