The use of an inspiratory impedance threshold valve (ITV) during active compression-decompression (ACD) cardiopulmonary resuscitation (CPR) improves perfusion pressures, and vital organ blood flow. We evaluated the effects of positive end-expiratory pressure (PEEP) on gas exchange, and coronary perfusion pressure gradients during ACD + ITV CPR in a porcine cardiac arrest model. All animals received pure oxygen intermittent positive pressure ventilation (IPPV) at a 5:1 compression-ventilation ratio during ACD + ITV CPR. After 8 min, pigs were randomized to further IPPV alone (n = 8), or IPPV with increasing levels of PEEP (n = 8) of 2.5, 5.0, 7.5, and 10 cm H2O for 4 consecutive min each, respectively. Mean ± SEM arterial oxygen partial pressure decreased in the IPPV group from 150 ± 30 at baseline after 8 min of CPR to 110 ± 25 torr at 24 min, but increased in the PEEP group from 115 ± 15 to 170 ± 25 torr with increasing levels of PEEP (P <0.02 for comparisons within groups). Mean ± SEM diastolic aortic minus diastolic left ventricular pressure gradient was significantly (P < 0.001) higher after the administration of PEEP (24 ± 0 vs 17 ± 1 mm Hg with 5 cm H2O of PEEP, and 26 ± 0 vs 17 ± 1 mm Hg with 10 cm H2O of PEEP), whereas the diastolic aortic minus right atrial pressure gradient (coronary perfusion pressure) was comparable between groups. Furthermore, systolic aortic pressures were significantly (P < 0.05) higher with 10 cm H2O of PEEP when compared with IPPV alone (68 ± 0 vs 59 ± 2 mm Hg). In conclusion, when CPR was performed with devices designed to improve venous return to the chest, increasing PEEP levels improved oxygenation. Moreover, PEEP significantly increased the diastolic aortic minus left ventricular gradient and did not affect the decompression phase aortic minus right atrial pressure gradient. These data suggest that PEEP reduces alveolar collapse during ACD ± ITV CPR, thus leading to an increase in indirect myocardial compression.