Although left ventricular dysfunction is common during ventilatory support with positive end-expiratory pressure (PEEP), the mechanism of this disorder remains unclear. In 10 patients with the adult respiratory-distress syndrome we studied the effects of a stepwise increase in PEEP from 0.to 30 cm H2O on left ventricular output, intracardiac transmural pressures, and two-dimensional echocardiographic measurements of left ventricular cross-sectional area at end-systole and at end-diastole. Increasing PEEP was associated with progressive declines in cardiac output, mean blood pressure, and left ventricular dimensions and with equalization of right and left ventricular filling pressures. The radius of septal curvature decreased at both end-diastole and end-systole, implying a leftward shift of the interventricular septum. At the highest PEEP, blood-volume expansion did not restore cardiac output, although left ventricular transmural filling pressures had returned to base-line values. We conclude that decreased cardiac output during PEEP is mediated by a leftward displacement of the interventricular septum, which restricts left ventricular filling.