The objective of this study is to evaluate the impact a change in anticoagulation protocol and circuit technology had on bleeding and thrombotic complications in patients supported on extracorporeal membrane oxygenation (ECMO). A retrospective review at a tertiary, academic pediatric intensive care unit was undertaken. The anticoagulation protocol changed from targeting an activated clotting time (ACT) to anti-Xa level. Significant changes in the ECMO circuit were undertaken concurrently. One-hundred and fifty-two ECMO runs in 129 patients in the ACT target group were compared with 122 ECMO runs in 101 patients in the anti-Xa target group. Improved probability of survival by ECMO duration, decreased rate of surgical exploration, increased time to first surgical exploration, decreased incidence of intracranial hemorrhage, increased time to identification of intracranial hemorrhage, decreased blood loss and transfused product volumes, decreased rate of circuit changes, and increased time to first circuit change were all observed in the anti-Xa targeted group. Heparin dosing was similar in both groups with fewer bolus doses of heparin and fewer changes in the infusion rate in the anti-Xa targeted group. The change in anticoagulation protocol and circuit technology was associated with an improvement in survival, a decrease in hemorrhagic complications, and a decrease in circuit changes.