To compare the effects of continuous negative extrathoracic pressure (CNEP) and positive end-expiratory pressure (PEEP) at the same level of transpulmonary pressure. Prospective analysis. Medical intensive care unit of a university hospital. Nine consecutive acute lung injury patients. Patients with cardiac failure and patients with chronic lung disease were excluded from the investigation. The patients were sedated and paralyzed while receiving mechanical ventilation and were studied in three different conditions: a) using a PEEP of 0 cm H2O (zero end-expiratory pressure); b) using a PEEP of 15 cm H2O; c) using CNEP. CNEP was applied to the thorax and the upper abdomen and its level was chosen to obtain a transpulmonary pressure similar to the one observed at a PEEP of 15 cm H2O. All patients had an arterial catheter, a pulmonary artery catheter, and a thermistor-tip fiberoptic catheter for thermo-dye-dilution in the femoral artery. These catheters were connected to an integrated monitoring system. We also placed an esophageal catheter in each patient to detect esophageal pressure. For each step, we assessed the hemodynamic variations by measuring intravascular pressures (via a pulmonary artery catheter), transmural pressures (computed by subtracting esophageal pressure from intravascular pressure), and blood volumes (derived from the technique of double indicator). The application of CNEP of -20+/-0.7 cm H2O produced a venous admixture and PaO2/FO2 improvement similar to that obtained with a PEEP of 15 cm H2O. This procedure is associated with a higher cardiac index (5.5+/-1.5 vs. 4.6+/-1.2 L/min/m2; p < .05) coupled with lower central venous pressure, pulmonary artery occlusion pressure, and higher transmural pressures and blood volume parameters. In acute lung injury patients, a CNEP of -20 cm H2O has the capability to obtain transpulmonary pressure and lung function improvement similar to a PEEP of 15 cm H2O. CNEP differs from the positive pressure by increasing the venous return and the preload of the heart, and has no negative effects on cardiac performance.