Hypoxia, energy deficit, and oxidative damage are principal mechanisms of injury in hemorrhagic shock (HS). Oxidant-induced cellular energetic failure and cell dysfunction is mediated, in part, via the activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS). Here we examine the effect of the PARS inhibitor 3-aminobenzamide (3AB) in a severe HS model. Pigs were bled to a cardiac index of 40 mL/kg/min for 2 h, which was followed by saline resuscitation (20 mL/kg). Hypovoiemia induced decreases in mean arterial blood pressure (to 40–42 mmHg), in both atrial pressures, in systemic oxygen consumption (by 26–30%), and in mixed venous saturation (by 65%). HS also caused lactic acidosis (4.0–5.5 mM). Fluid replacement with saline caused only a partial and transient recovery of blood pressure and cardiac output, with no recovery of stroke work during resuscitation. Fluid replacement did not prevent the progressive hemodynamic decompensation. The PARS inhibitor 3AB (15 mg/kg) significantly ameliorated the fall in blood pressure, cardiac output, and stroke work; slightly increased left atrial pressure during resuscitation; and significantly prolonged survival. PARS inhibition also prevented the reduction in oxygen consumption and mixed venous saturation during resuscitation. Taking these data together, we conclude that pharmacological inhibition of PARS exerts beneficial effects in a porcine model of severe HS. We propose that favorable action of 3AB is related, at least in part, to an improved cardiac performance.