BACKGROUND/PURPOSE: Intracranial hemorrhage (ICH), is a major source of morbidity and the leading cause of death in neonates treated with extracorporeal membrane oxygenation (ECMO). Anecdotal reports have suggested that epsilon-aminocaproic acid (EACA) can decrease the risk of ICH. The purpose of this study was to evaluate, in a multiinstitutional, prospective, randomized, blinded fashion, the effect of EACA on the incidence of hemorrhagic complications in neonates receiving ECMO. METHODS: All neonates (except congenital diaphragmatic hernia) who met criteria for ECMO at three institutions were eligible for enrollment. EACA (100 mg/kg) or placebo was given at the time of cannulation followed by 25 mg/kg/h for 72 hours. Bleeding complications, transfusion requirements, and thrombotic complications were recorded. Post-ECMO imaging included head ultrasound scan computed tomography (CT) scan, and duplex ultrasound scan of the inferior vena cava and renal vessels. RESULTS: Twenty-nine neonates were enrolled (EACA, 13 and placebo, 16). Five (17.2%) patients had a significant (grade 3 or larger) ICH. There was no statistical difference in the incidence of significant ICH in patients who received EACA (23%) versus placebo (12.5%). Septic patients accounted for all of the ICH in the EACA group. Thrombotic complications (aortic thrombus and SVC syndrome) developed in two patients from the placebo group. There was no difference in thrombotic circuit complications between groups. CONCLUSIONS: Our results suggest that the use of EACA in neonates receiving ECMO is safe but may not decrease the overall incidence of hemorrhagic complications.