Survival after hypovolemic shock and cardiac arrest is dismal with current therapies. We evaluated the potential benefits of vasopressin versus large-dose epinephrine in hemorrhagic shock and cardiac arrest on vital organ perfusion, and the likelihood of resuscitation. In 18 pigs, 35% of the estimated blood volume was withdrawn over 15 min and ventricular fibrillation was induced 5 min later. After 4 min of cardiac arrest and 4 min of standard cardiopulmonary resuscitation, a bolus dose of either 200 μg/kg epinephrine (n = 7), 0.8 unit/kg vasopressin (n = 7), or saline placebo (n = 4) was administered in a blinded, randomized manner. Defibrillation was attempted 2.5 min after drug administration, and all animals were subsequently observed for 1 h without further intervention. Spontaneous circulation was restored in 7 of 7 vasopressin animals, in 6 of 7 epinephrine pigs, and in 0 of 4 placebo swine. At 5 and 30 min after return of spontaneous circulation, median (minimum and maximum) renal blood flow after epinephrine was 2 (0-31), and 2 (0-48) mL · 100 g-1 · min-1, respectively; and after vasopressin 96 (12-161), and 44 (16-105) mL · 100 g-1 · min-1, respectively (P < .01 between groups). Epinephrine animals developed a profound metabolic acidosis by 15 min after return of spontaneous circulation (mean arterial pH, 7.11 ± 0.01), and by 60 min all epinephrine-treated animals had died. The vasopressin pigs had (P = 0.015) less acidosis (pH = 7.26 ± 0.04) at corresponding time points, and all survived ≥55 min (P < 0.01). In conclusion, treatment of hypovolemic cardiac arrest with vasopressin, but not with large-dose epinephrine or saline placebo, resulted in sustained vital organ perfusion, less metabolic acidosis, and prolonged survival. Based on these findings, clinical evaluation of vasopressin during hypovolemic cardiac arrest may be warranted.