Although extracorporeal membrane oxygenation (ECMO) improves oxygenation, pulmonary vascular resistance may be increased due to endothelial function impairment. Inhaled nitric oxide (iNO) is increasingly used for treatment of pulmonary hypertension after surgical repair of congenital heart defects, with or without ECMO. One of the main complications of its application is deterioration of oxygenation following withdrawal of iNO. To test whether intravenous prostacyclin applied prior to and during iNO withdrawal can mitigate this rebound effect, we conducted a retrospective case control study. The rebound effect was defined as a 5% decrease of oxygenation saturation within 4 h after iNO withdrawal. Twelve children suffering from pulmonary hypertension (2 after ECMO) and treated with iNO received 10 ng/kg/min prostacyclin intravenously 24 h prior to iNO withdrawal (Group 1). Twelve children treated with iNO (3 after ECMO) who received no prostacyclin prior to iNO withdrawal were matched as controls. The rebound effect occurred in 1 out of 12 children in Group 1 and in 8 out of 12 children in Group 2 (p = 0. 0039). We conclude that application of intravenous prostacyclin prior to and during iNO withdrawal may be able to mitigate the rebound effect.