Sildenafil is a pulmonary anti-hypertensive agent whose action could be modified by different fractions of inspired oxygen (FiO 2 ). We compared the effects of pure oxygen (FiO 2 >90%) or room air (21% FiO 2 ) on the cardiopulmonary actions of sildenafil in sheep with acute pulmonary embolism (APE).Forty anesthetized, mechanically ventilated sheep (34.9±5.4kg), were randomly distributed into four groups (n=4 per group): FiO 2 >90% without intervention; APE induced by microspheres with FiO 2 >90%, followed 30min later by placebo (Emb 90 ); or APE followed 30min later by intravenous sildenafil (0.7mg/kg over 30min) with FiO 2 >90% (Emb+Sild 90 ) or 21% FiO 2 (Emb+Sild 21 ). Variables were recorded until 30min after the end of treatment administration.Microsphere injection increased (P<0.05) mean pulmonary artery pressure (MPAP) in all embolized groups (111–140% higher than that of baseline). Compared with values recorded 30min after induction of APE (E 30 ), sildenafil induced greater decreases in MPAP in the Emb+Sil 90 group than in the Emb+Sil 21 group (23% and 14% lower than E 30 , respectively). Hypotension (mean arterial pressure<60mmHg) was precipitated by sildenafil due to systemic vasodilation in the Emb+Sil 21 group. Embolization lowered the PaO 2 /FiO 2 ratio and increased venous admixture, but sildenafil did not alter the oxygenation impairment induced by APE.Sildenafil induces a more consistent pulmonary anti-hypertensive effect and causes less interference with the systemic circulation with the concomitant use of pure oxygen than that with room air in the APE setting.