The predominant mechanism of the cardiac output reduction associated with positive end-expiratory pressure (PEEP) is unclear. Reported possibilities include decreased systemic venous return, increased pulmonary vascular resistance, or change in ventricular contractility. We investigated this question by studying 9 patients with the adult respiratory distress syndrome (ARDS) during PEEP application. We used an equilibrium radionuclide angiography method modified for improved right ventricular imaging to evaluate changes in left and right ventricular volume and contractility. Thermodilution cardiac output and stroke volume progressively declined (27 and 33% mean decrease, respectively) with increasing increments of PEEP. Right and left ventricular end diastolic counts, reflecting volume, also progressively diminished as PEEP increased (38 and 27% mean decrease in RV and LV counts, respectively; p less than 0.001 for both ventricles). A slight upward trend in ejection fraction was found for both ventricles. These findings support the concept that during PEEP application the reduction in cardiac output is due to biventricular reduction in blood volume. This biventricular volume reduction is compatible with either preload reduction to both ventricles because of impeded venous return or to change in ventricular configuration caused by external compression of both ventricles.