Patients undergoing veno-arterial extracorporeal membrane oxygenation (VA-ECMO) typically suffer from cardiogenic pulmonary edema and lung atelectasis, which can exacerbate right ventricular (RV) dysfunction through an increase in lung elastance and RV afterload. Invasive mechanical ventilation settings, and positive end-expiratory pressure (PEEP) in particular, can help to improve RV performance by optimizing lung recruitment and minimizing alveolar overdistention. In this report, we present a VA-ECMO supported patient in whom in vivo RV pressure-volume (PV) loops were measured during a decremental PEEP trial, leading to the identification of an optimum PEEP level from a cardio-respiratory viewpoint. This innovative approach of tailoring mechanical ventilation settings according to cardio-respiratory physiology through in vivo RV PV loops may provide a novel way to optimize hemodynamics and patient outcomes.