Hemorrhage related to systemic heparinization is the major complication of extracorporeal membrane oxygenation (ECMO). Intracranial hemorrhage (ICH) is the most devastating complication. ICH developed in 13 of our 25 ECMO patients (52%). Six died, six survived with normal neurologic function, and one is severely impaired. In nine of 13 patients (69%) ECMO was discontinued when serial cranial ultrasounds showed progressive ICH. Seizures developed in six infants while receiving ECMO, and ICH developed in all. There is a correlation between hypertension and ICH. A hypertension index (hours systolic BP greater than 90/hours receiving ECMO) was 0.1 +/- 0.12 for infants without ICH and 0.37 +/- 0.28 for infants with ICH (P less than .05). ICH developed in 79% of the patients with an index greater than 0.1. Twenty neck explorations were required in the first 20 patients for incisional bleeding (mean blood loss, 21.9 +/- 18.0 mL/kg/d). We now use fibrin glue following cannulation and have done only one neck exploration in the last five patients (mean blood loss, 2.8 +/- 2.2 mL/kg/d, P less than .05). Endobronchial bleeding has responded to phenylephrine lavage and increased positive end-expiratory pressure. We have controlled pleural space bleeding with topical thrombin. None of the hemorrhagic complications encountered correlate with the activated clotting time or the amount of heparin used. There is an increased risk of hemorrhage associated with platelet counts less than 100,000/microL for 75% of a day (P less than .05) so that aggressive platelet transfusion remains important in preventing hemorrhagic complications during ECMO.