Persistent pulmonary hypertension (PPH) together with pulmonary hypoplasia accounts for high mortality among patients with congenital diaphragmatic hernia (CDH). Endothelin (ET) is a recently described endothelium-derived vasoconstrictor peptide with a potent and sustained effect. The authors examined plasma ET levels in eight patients with CDH who had respiratory distress at birth and in 15 age-matched controls. The plasma ET levels were measured using a highly sensitive and specific enzyme immunometeric assay (EIA) preoperatively, intraoperatively, and 24 and 48 hours postoperatively. The mean preoperative plasma ET level (53.9 +/- 21.1 pg/mL) of the patients was significantly (P < .01) higher than that of controls (5.9 +/- 4.5 pg/mL). Two patients who died before operation had plasma ET levels of 60 pg/mL and 82 pg/mL, respectively. Three patients who had PPH postoperatively continued to have high ET levels, and at 48 hours, the mean plasma ET level in these patients was 33 pg/mL. In contrast, in the three patients who survived after repair of CDH, the mean plasma ET level at 48 hours was 1.3 pg/mL. The authors further examined the lungs of two patients who died before operation for the expression of ET, using immunocytochemistry. Pulmonary endothelial cells had strong ET staining compared with control tissues. These findings suggest that ET may be a pathophysiological mediator of pulmonary hypertension in patients with CDH.