The objective of the present study was to evaluate the effects of inhaled and intravenous sildenafil on the pulmonary endothelium-dependent relaxations, the hemodynamic profile and oxygenation after cardiopulmonary bypass. Five groups of Landrace swine were compared: 1) control; 2) cardiopulmonary bypass: 90 min of normothermic cardiopulmonary bypass; 3) precardiopulmonary bypass sildenafil nebulization; 4) postcardiopulmonary bypass sildenafil nebulization; 5) intravenous sildenafil administration prior to cardiopulmonary bypass. All groups underwent a 60-min period of pulmonary reperfusion after cardiopulmonary bypass. Vascular reactivity of second-degree pulmonary arteries was evaluated in response to acetylcholine and bradykinin. Cardiopulmonary bypass caused a significant decrease in endothelium-dependent relaxations to both agonists; this dysfunction was prevented by administration of sildenafil, both intravenous and inhaled (P < 0.05). Both administration routes prevented the significant increase in mean pulmonary arterial pressure with a safe hemodynamic profile. Moreover, intravenous and inhaled sildenafil after cardiopulmonary bypass also prevented the increase in alveoloarterial gradient (P < 0.05). Both sildenafil formulations of administration prevent the occurrence of pulmonary endothelial dysfunction. Depending on the administration moment and the route, the administration of sildenafil improves the hemodynamic profile and post-cardiopulmonary bypass oxygenation.