To investigate the contribution of local mechanical factors to the alteration in ventricular function that occurs during ventilation with positive end-expiratory pressure (PEEP), the hemodynamic effects of increasing end-expiratory pressure with both lungs ventilated, and with the upper lobes, lower lobes, right and left lungs selectively ventilated, were examined in 20 anesthetized open-chest dogs. The rise in pressure between the lungs and heart exceeded that of the ipsilateral atrium. Increasing PEEP with both lungs ventilated caused atrial and mediastinal (juxtacardiac) pressures to increase and stroke volume to decrease more than with ventilation of smaller lung volumes. Patterns causing distention of lung tissue adjacent to the right heart were associated with the greatest decrease of stroke volume. Decreasing stroke volume related more closely to increasing right atrial than to left atrial pressure. We concluded that juxtacardiac pressure increases markedly as the lungs distend, even in an open-chest preparation, and that preload reduction on this basis, not ventricular impairment, best explains diminished cardiac output during ventilation with PEEP.