OBJECTIVE To report a case of intermediate-probability suspected heparin-induced thrombocytopenia (HIT) treated with lepirudin in a patient requiring continuous extracorporeal membranous oxygenation (ECMO). CASE SUMMARY A 17-year-old girl was admitted with multiple traumatic injuries including severe bilateral pulmonary contusions. Within 48 hours, she developed progressive pulmonary failure despite mechanical ventilation, and was placed on ECMO. Anticoagulation of the ECMO circuit was facilitated by unfractionated heparin (UFH). The platelet count of 116 × 10³/mm³ after initiation of ECMO gradually decreased over 5 days to 44 × 10³/mm³. On ECMO day 5, a highly positive enzyme-linked immunosorbent assay for HIT antibodies was reported, and the UFH infusion was discontinued. Lepirudin was immediately started with a bolus of 0.1 mg/kg, followed by an infusion of 0.12 mg/kg/h, with a target activated partial thromboplastin time (aPTT) ratio approximately 2 times control. The ECMO circuit was maintained without any unexpected bleeding complications or thrombosis for 6 additional days until the patient died secondary to pulmonary failure after ECMO was removed. DISCUSSION Use of ECMO typically requires continuous infusion of UFH to keep the circuit from clotting. In patients with HIT, alternative anticoagulation using a direct thrombin inhibitor may be warranted. Lepirudin was effectively used to maintain the circuit despite continued presence of heparin molecules impregnated into the ECMO circuit tubing. The aPTT was successfully used to monitor and adjust the lepirudin infusion. CONCLUSIONS In patients requiring ECMO in the presence of HIT, anticoagulation of the ECMO circuit may be accomplished using a continuous infusion of a direct thrombin inhibitor such as lepirudin.