Cardiovascular dysfunction in asphyxiated neonates contributes significantly to their morbidity and mortality. We have recently shown that a low-dose vasopressin infusion (0.005 - 0.01 units/kg per hour) may improve myocardial oxygen transport balance in a swine model of neonatal hypoxia-reoxygenation. We aimed to compare the systemic and regional hemodynamic effects of low-dose vasopressin to dobutamine, a synthetic beta-adrenoreceptor agonist. Piglets (1 - 5 days old, 1.6 - 2.2 kg) were anesthetized and instrumented to continuously monitor systemic hemodynamic parameters, including cardiac output and mesenteric flow indices. After 2 h of hypoxia (10% - 15% O2), piglets had normoxic reoxygenation for 4 h. In a blinded randomized fashion, piglets received infusion of either vasopressin (0.01 units/kg per hour started at 30 min of reoxygenation) or dobutamine (20 μg/kg per minute started at 2 h of reoxygenation) (n = 8 per group). Hypoxia-reoxygenation controls (placebo, n = 8) and sham-operated (n = 5) piglets were also studied. Tissue lactate, glutathione, glutathione disulfide, and lipid hydroperoxides levels and histology of the left ventricle and the small bowel were analyzed. Plasma was also analyzed for troponin-I and intestinal fatty acid-binding protein levels. Piglets subjected to hypoxia-reoxygenation had cardiogenic shock and metabolic acidosis, which improved on reoxygenation. During recovery, cardiac output and mesenteric flows gradually deteriorated and were increased similarly in vasopressin- and dobutamine-treated piglets (P < 0.05 vs. controls). Plasma troponin-I and left ventricular lactate levels were lower in the vasopressin and dobutamine groups (P < 0.05 vs. controls), with no difference in the histological analysis among groups. The intestinal GSSG/GSH ratio and lipid hydroperoxides level were lower in the vasopressin and dobutamine groups (P < 0.05 vs. controls). This study is the first to demonstrate that a low-dose vasopressin infusion used in the setting of neonatal swine model of hypoxia-reoxygenation is associated with an improvement in cardiac output and mesenteric perfusion.