BACKGROUND Post-cardiopulmonary bypass (CPB) lung injury is the combination of whole body inflammatory response and local ischemia-reperfusion (IR) injury. We investigated the benefit of pulmonary perfusion with L-arginine in protection against post-CPB lung injury. METHODS New Zealand white rabbits (n = 50, weight, 2.5-2.8 kg) were divided into five groups (n = 10 each): sham (sham sternotomy), CPB (CPB without pulmonary perfusion), perfusion (CPB with pulmonary perfusion), L-arginine (CPB with perfusion + L-arginine), and L-NAME (CPB with perfusion + L-NAME). The duration of CPB was 60 min followed by 2 h of reperfusion. Pulmonary perfusion was performed every 20 min through the pulmonary artery during CPB. Checking parameters included: (1) pulmonary vascular resistance, (2) pulmonary artery endothelium relaxation (organ chamber study), and (3) IR marker (myeloperoxidase) and inflammatory markers (TNF-α, IL-B, NF-κB). RESULTS CPB induced pulmonary artery endothelium dysfunction manifested by increased pulmonary vascular resistance and impaired pulmonary artery relaxation. Pulmonary perfusion could significantly reverse the phenomenon (P < 0.01) while provision of NO precursor-L-arginine with pulmonary perfusion together further possessed significant relaxation ability for pulmonary arterial endothelium compared with perfusion alone (P < 0.05). Accordingly, lung parenchyma myeloperoxidase activity and inflammatory cytokine level were also markedly increased after CPB (P < 0.05). Pulmonary perfusion could partially decrease the response, whereas additional L-arginine further attenuated inflammatory cytokine release (P < 0.05). CONCLUSIONS Pulmonary perfusion during CPB partially ameliorates CPB-induced lung injury. Pulmonary perfusion with L-arginine could further attenuate lung injury by restoring endothelial function and decreasing inflammatory response.