Pulmonary hemorrhage (PH) occurs infrequently as a complication in neonates with respiratory failure. Major PH has been observed at the authors' institution in several neonates after "successful" completion of extracorporeal life support (ECLS) therapy. The authors sought to determine the incidence of PH and the risk factors associated with this unique and newly described morbidity after ECLS. The hospital records of all patients who had PH after ECLS were reviewed. The control patients were the first three infants who underwent ECLS just before each PH case. PH was defined as the occurrence of bloody tracheal secretions associated with a deterioration in pulmonary status. Demographics, ventilator/ECLS parameters, fluid management, coagulation, and laboratory studies were evaluated in the pre-ECLS, during ECLS, and in the post-ECLS period. From 1985 to 1993, 13 (6%) of 214 neonates suffered major PH, at a mean time of 43.2 +/- 9.2 hours after the ECLS course. The overall mortality rate for children with PH was 38%, compared with 5% among the control patients. In the pre-ECLS phase, patients with PH required more fluid (153.6 +/- 20.2 mL/kg/d v 106.8 +/- 10.2 mL/kg/d) and were acidemic for a longer period (2.3 +/- 1.2 hours v 0.6 +/- 0.2 hours; pH < 7.25). No differences were noted in AaDo2 or oxygenation index criteria. During ECLS, inotropes were required more often (23% v 0%; P < .01) because hypotension was more common (77% v 33%; P < .05). Activated clotting times (ACT) and heparin requirements were equivalent for the two groups. After ECLS the patients with PH required longer ventilatory assistance (184.9 +/- 48.2 hours v 83.4 +/- 16.7 hours) and supplemental oxygen (24.3 +/- 3.0 days v 17.2 +/- 1.9 days). No coagulation abnormalities were identified at the time of PH. Higher SGPT (185.4 +/- 146.4 U/L v 22.6 +/- 3.5 U/L; P < .05) and BUN (69.3 +/- 7.5 mg/dL v 47.2 +/- 5.9 mg/dL; P < .05) also were noted for the patients with PH. PH represents an important and novel morbidity in neonates after ECLS. Prolonged acidosis, a high fluid requirement before ECLS, the need for blood pressure support during ECLS, and evidence of renal and/or hepatic dysfunction serve to identify patients who have a high risk for the development of this complication.