The intrathoracic pressure regulator (ITPR) (CirQLator; Advanced Circulatory Systems Inc, Roseville, Minn) is a novel, noninvasive device intended to increase cardiac output and blood pressure in hypovolemic or cardiogenic shock by generating a continuous low-level intrathoracic vacuum in between positive pressure ventilations. Although there are robust data supporting the benefit of the ITPR in multiple animal models of shock, the device has not been used in humans. The goals of this study were to evaluate both the safety and efficacy of the ITPR in humans. Twenty patients undergoing coronary artery bypass graft surgery were enrolled in this phase 1 study. Intraoperative use of both pulmonary artery pressure monitoring and transesophageal echocardiography (TEE) was required for study inclusion. Hemodynamic variables as well as TEE measurements of left ventricular performance were collected at baseline and after the ITPR device was activated, before surgical incision. Thermodilution cardiac output increased significantly with the application of the ITPR (4.9 vs. 5.5 L/min; P = 0.017). Similarly, cardiac output was measured by TEE (5.1 vs. 5.7 L/min; P = 0.001). There were significant increases in pulmonary artery systolic blood pressures (35 vs. 38 mmHg; P < 0.001) and mean pulmonary artery pressures (24 vs. 26 mmHg; P = 0.008). There were no significant differences in systemic blood pressures, left ventricular volumes, stroke volume, or ejection fraction as measured by TEE. Using two different measurement techniques, application of the ITPR increased cardiac output in normovolemic anesthetized patients who underwent coronary artery bypass graft before sternotomy. These data suggest that the ITPR has the potential to safely and effectively increase cardiac output in humans.