Background: Extracorporeal membrane oxygenation (ECMO) is a lifesaving intervention for patients with refractory respiratory failure and/or shock and can be provided via a venovenous (VV) or venoarterial (VA) circuit. Application of ECMO exposes the patient to a number of complications ranging from hemorrhage to infection. Thrombocytopenia is one such complication. Due to the need for systemic anticoagulation with unfractionated heparin (UFH), those treated with ECMO may be at risk for heparin-induced thrombocytopenia (HIT). Incidence of HIT in ECMO is <1%. Being a rare entity, HIT syndrome in ECMO presents as a unique diagnostic and therapeutic challenge. Case description: A 45-year-old male, a known smoker, presented to the hospital with complaints of fever and cough for 1 week and grade 4 breathlessness for 1 day. He was diagnosed as acute respiratory distress syndrome (ARDS) with H1N1 positive, and treatment was initiated accordingly. However, during the course of his stay in the intensive care unit (ICU), his oxygenation worsened. He was upgraded to high-flow nasal cannula (HFNC) support but had to be eventually intubated and mechanically ventilated as his respiratory mechanics were not improving. In view of refractory hypoxemia, VV ECMO was initiated with heparin infusion on flow. Initially, an improvement in oxygenation was witnessed, but 2 days post initiation of ECMO, complications raised in the form of thrombocytopenia, recurrent oxygenator failure (clotting), and deep vein thrombosis (DVT) of the right femoral vein. Even though initial suspicion was of sepsis-induced thrombocytopenia, the presence of thrombosis with 4T score of 7 strongly favored HIT syndrome, and diagnosis was confirmed by laboratory testing. Immediately, the circuit and oxygenator were changed, and heparin infusion was replaced with bivalirudin infusion. The patient developed ventilator-associated pneumonia as well as transfusion-related acute lung injury (TRALI) due to multiple transfusions. Antibiotics were escalated accordingly, and he underwent tracheostomy, anticipating prolonged ventilator period. Slowly, his oxygenation improved. After 28 days of VV ECMO, he was weaned off the ventilator and ECMO and was discharged home. Conclusion: The challenges faced in this case drive home the fact that HIT syndrome must be the first among the differentials when a patient on ECMO develops thrombocytopenia, and the timely diagnosis and management of HIT are very crucial for a good outcome.