The purpose of the study was to test the hypothesis that diaspirin cross-linked hemoglobin (DCLHb) can produce improved resuscitation during cardiac arrest. DCLHb, a derivative of human hemoglobin, has previously been demonstrated to produce a vasopressor response that is associated with increased blood flow to vital organs. In addition, it is an oxygen carrier. These effects may be beneficial to extreme low flow states, such as that during cardiac arrest and cardiopulmonary resuscitation (CPR). Experimental cardiac arrest and CPR were carried out in 32 anesthetized immature pigs. In each animal, ventricular fibrillation was induced for 5 min, followed by 10 min of standard CPR with a pneumatic device and room air ventilation. High (15 ml/kg) and low (5 ml/kg) doses of DCLHb or equivalent volume of normal saline were infused at the beginning of CPR in a random and blind manner. Cardiac output, organ blood flow, aortic pressure, coronary perfusion pressure, blood gases, and lactate concentrations were obtained before and during CPR. Following the 10-min CPR, the animals were defibrillated and the return of spontaneous circulation (ROSC) determined. DCLHb treatment achieved 75% ROSC compared with 25% in the saline group (p < 0.05). In addition, a better (p < 0.05) myocardial O(2) delivery, venous blood O(2) content, and myocardial and cerebral perfusion pressure were observed in the DCLHb group. DCLHb treatment during cardiac arrest and CPR significantly improves ROSC. This is most likely related to its improvement in coronary perfusion and myocardial oxygen delivery.