The optimum heparin monitoring method during extracorporeal membrane oxygenation (ECMO) is unknown. We report a protocol utilizing only anti-factor Xa (anti-Xa) to manage anticoagulation in 22 consecutive ECMO patients. Anti-Xa was monitored with heparin titration every hour until goal 0.4-0.8 IU/ml. Once therapeutic, monitoring was progressively spaced up to every 6 hours. Patients received frequent antithrombin III (ATIII). Extracorporeal membrane oxygenation indications were as follows: 13 cardiorespiratory failures, eight extracorporeal cardiopulmonary resuscitations (ECPRs), and one pulmonary hypertension. Median weight was 4 kg, age 12.5 days, and ECMO duration 88 hours. Survival was 50%. Mean heparin dose was 38 ± 11 unit/kg/hr. Eight patients received no heparin for median 9 hours because of postoperative bleeding. Compared with prior activated clotting time (ACT) protocol, there were 20 fewer blood draws per day to manage anticoagulation, p < 0.001. Only 9% of the anti-Xa levels were outside therapeutic range versus 22% using ACT, p < 0.01. Six patients had bleeding complications, and seven had oxygenator change-out. Change-out was associated with blood product administration and bleeding but not with heparin-free period (p = 0.39). Survival to discharge was higher among those who did not require circuit/oxygenator change-outs, 4/7 versus 7/7 (p < 0.01). Anti-factor Xa-based ECMO heparin management protocol is feasible, decreases blood sampling and heparin infusion adjustments, and does not appear to increase complications.