Competitive flows syndrome result in severe regional hypoxemia when the deoxygenated flow from the native left ventricle (LV) competes with oxygenated flow from extracorporeal life support (ECLS) pump with potentially severe consequences for the cerebral and coronary circulations. Fast correction of hypoxemia could be obtained by decreasing native LV flow by infusion of a short-acting beta-blocker (esmolol). Our purpose was to retrospectively review the efficacy of esmolol in this situation and hypothesize on the potential mechanisms of action and the associated risks. This is a retrospective analysis of five clinical cases, who underwent lung transplantation and a femoro-femoral venoarterial (VA) ECLS. The patients presented severe hypoxemia (SpO2 < 85%) measured through photoplethysmography on a right hand finger. From the patients' medical records and anesthesia flowcharts, hemodynamic, right heart catheterization, echocardiography variables, and arterial blood gas results were noted before and after injection of esmolol. Mechanical ventilation and VA ECLS function variables were optimized and unchanged before and after esmolol injection. All patients had terminal respiratory failure with pulmonary hypertension and conserved LV systolic function. Immediately following esmolol injection (1.3 ± .7 mg/kg; mean ± 1 SD), SpO2 increased from 73% ± 12 to 95% ± 6; blood to arterial partial pressure in CO2 (PaCO2) decreased from 52 ± 18 to 35 ± 7 mmHg systolic pulmonary artery pressure decreased from 61 ± 8 to 50 ± 12 mmHg; the pulmonary artery oxygen saturation (SvO2); increased from 51% ± 24 to 77% ± 12; systemic arterial pressure or catecholamine requirements were unchanged. In conclusion, these results suggest that injection of esmolol allowed rapid correction of regional hypoxemia occurring during lung transplantation despite femoro-femoral VA ECLS. The mechanism is probably a decreased cardiac output of the native LV due to esmolol-induced negative inotropic and chronotropic effects without significant adverse effects on systemic tissue perfusion.