Acute lung injury still accounts for postoperative mortality after cardiopulmonary bypass (CPB). The safety and the efficacy of pulsatile pulmonary perfusion (PPP) during CPB were analyzed. Preliminary results of the first PPP trial in human beings are reported. Thirty low-risk coronary artery bypass grafting (CABG) patients were prospectively randomized to receive PPP with oxygenated blood during CPB and aortic cross-clamping (15 patients, PPP-group) or to conventional CPB (15 patients, control group). Alveolo-arterial oxygen gradient (A-aDO(2)) was set as the primary end point and collected preoperatively, at intensive care unit (ICU) arrival (T1), 3h postoperatively (T2), and post extubation (T3). Secondary end points were collected at the same time points and consisted of respiratory indices (partial pressure of arterial oxygen/fraction of inspired O(2) (PaO(2)/FiO(2)), lung compliance, mixed-venous partial pressure of oxygen (pO(2))) and hemodynamic pulmonary parameters (indexed pulmonary vascular resistances (PVRI), pulmonary arterial pressure (PAP), pulmonary capillary wedge pressure (PCWP), and cardiac index (CI)). Bronchoalveolar lavage (BAL) fluid was collected preoperatively, at ICU arrival (T1-BAL) and after 4h. There were no PPP-related complications. Patients undergoing PPP showed a better preserved A-aDO(2) (group-p=0.001) throughout the study period (group × time-p = 0.0001). PaO(2)/FiO(2) and lung compliance were better preserved by PPP (group-p and group × time-p ≤ 0.05 for all). Pulmonary hemodynamic status was positively influenced by PPP, as shown by the higher CI (group-p=0.0001, group × time-p = 0.0001), and the lower PVRI, PAP, and PCWP (group-p ≤0.001, group × time-p=0.0001 for all). Postoperative BAL specimens demonstrated a lower absolute count of white blood cells (group-p=0.0001), a higher percentage of monocytes/macrophages (group-p=0.027), and a lower percentage of neutrophils (group-p=0.015) after PPP. Oxygenated blood PPP proved safe and significantly ameliorated pulmonary hemodynamic parameters and respiratory indices in low-risk CABG.