A 51-year-old man developed severe respiratory failure refractory to conventional treatment, confirmed by influenza A virus, and bilateral pneumonia with pulmonary edema on chest CT after 9 days of fever and cough. Veno-venous ECMO was started due to low oxygenation (PaO₂/FiO₂ 48.9 mmHg). During ECMO, severe mixed hyperbilirubinemia with a hemolytic component developed, where total bilirubin reached a maximum of 887 μmol/L. Immunohematological tests confirmed immune-mediated hemolysis (positive direct and indirect antiglobulin tests). Treatment included hepatoprotective drugs, dual plasma molecular adsorption system (DPMAS) and therapeutic plasma exchange. After ECMO decannulation, bilirubin levels returned to normal, the patient was weaned from ventilation, transferred to a regular ward, and discharged with full social reintegration. The case highlights the diagnostic challenge between mechanical and immune hemolysis in ECMO and the success of combination therapy.