Based upon the hypothesis that vasopressin (antidiuretic hormone) may increase vascular resistance during ventricular fibrillation, the effects of this potent vasoconstrictor were studied in a porcine model of ventricular fibrillation. Vasopressin therapy was compared to epinephrine by randomly allocating 14 pigs to receive either 0.045 mg/kg of epinephrine (n = 7) or 0.8 U/kg of vasopressin (n = 7) after 4 min of ventricular fibrillation and 3 min of open-chest cardiopulmonary resuscitation. During cardiopulmonary resuscitation, myocardial blood flow before and 90 s and 5 min after drug administration was 57 ± 11, 84 ± 11, and 59 ± 9 mL · min-1 · 100 g- 1 (mean ± SEM) in the epinephrine group, and 61 ± 5, 148 ± 26, and 122 ± 22 mL · min-1 · 100 g-1 in the vasopressin group (P < 0.05 at 90 s and 5 min). At the same times, mean cardiac index was not significantly different between the groups. After drug administration, coronary venous PCO2 was significantly higher and coronary venous pH was significantly lower in the epinephrine as compared to the vasopressin group. All pigs in both groups were resuscitated and survived the 2-h observation period. We conclude that vasopressin improves vital organ perfusion during ventricular fibrillation and cardiopulmonary resuscitation. Vasopressin seems to be at least as effective as epinephrine in this pig model of ventricular fibrillation.