Background-Despite improving arterial oxygen saturation and pH, bystander cardiopulmonary resuscitation (CPR) with chest compressions plus rescue breathing (CCϩRB) has not improved survival from ventricular fibrillation (VF) compared with chest compressions alone (CC) in numerous animal models and 2 clinical investigations. Methods and Results-After 3 minutes of untreated VF, 14 swine (32Ϯ1 kg) were randomly assigned to receive CCϩRB or CC for 12 minutes, followed by advanced cardiac life support. All 14 animals survived 24 hours, 13 with good neurological outcome. For the CCϩRB group, the aortic relaxation pressures routinely decreased during the 2 rescue breaths. Therefore, the mean coronary perfusion pressure of the first 2 compressions in each compression cycle was lower than those of the final 2 compressions (14Ϯ1 versus 21Ϯ2 mm Hg, PϽ0.001). During each minute of CPR, the number of chest compressions was also lower in the CCϩRB group (62Ϯ1 versus 92Ϯ1 compressions, PϽ0.001). Consequently, the integrated coronary perfusion pressure was lower with CCϩRB during each minute of CPR (PϽ0.05 for the first 8 minutes). Moreover, at 2 to 5 minutes of CPR, the median left ventricular blood flow by fluorescent microsphere technique was 60 mL · 100 g Ϫ1 · min Ϫ1 with CCϩRB versus 96 mL · 100 g Ϫ1 · min Ϫ1 with CC, PϽ0.05. Because the arterial oxygen saturation was higher with CCϩRB, the left ventricular myocardial oxygen delivery did not differ. Conclusions-Interrupting chest compressions for rescue breathing can adversely affect hemodynamics during CPR for