Positive end-expiratory pressure (PEEP) commonly decreases cardiac output. The major cause of this is believed to be decreased venous return due to increased right atrial pressure. We hypothesized that when the lungs were hyperinflated they could also restrict venous return by directly compressing the thoracic vena cavae. We measured the longitudinal distribution of pressure in the thoracic vena cavae of 10 dogs on and off 10 mm Hg PEEP, in the supine (S), prone (P), right lateral (RL), and left lateral decubitus (LL) positions. In the superior vena cava (SVC) both on and off PEEP, and in the inferior vena cava (IVC) off PEEP, pressure fell uniformly from the thoracic inlet to the right atrium. However, in the IVC on PEEP, intravascular pressure fell abruptly by up to 5 mm Hg. This pressure drop occurred in a discrete (1 to 2-cm) segment of the IVC, suggesting a localized increase in extravascular surface pressure. When this pressure inflection was present, changes in right atrial pressure had no effect on pressure in the IVC upstream of the inflection, consistent with a “vascular waterfall.” These observations were most prominent in the LL, least common in the RL, and variably present in the P and S positions. Occlusion of the right bronchus intermedius prior to PEEP (preventing right lower, middle, and accessory lobe inflation) prevented the appearance of the pressure inflection during PEEP in the LL but not in the S or P positions. We conclude that PEEP impedes venous return partly by direct compression of the IVC, predominantly in positions in which the IVC is non-dependent. This may be due to hyperinflation of lobes of the right lung.