Extracorporeal membrane oxygenation (ECMO) is increasingly used to treat cardiopulmonary failure in critically ill patients. Peripheral cannulation may be complicated by a persistent low cardiac output in case of veno-venous cannulation (VV-ECMO) or by differential hypoxia (e.g., lower PaO2 in the upper than in the lower body) in case of veno-arterial cannulation (VA-ECMO) and severe impairment of pulmonary function associated with cardiac recovery. The treatment of such complications remains challenging. We report the early effects of the use of veno-arterial-venous (V-AV) ECMO in this setting. Methods: Retrospective analysis including patients from five different European ECMO centers (January 2013 to December 2016) who required V-AV ECMO. We collected demographic data as well as comorbidities and ECMO characteristics, hemodynamics, and arterial blood gas values before and immediately after (i.e., within 2 h) V-AV implementation. Results: A total of 32 patients (age 53 (interquartiles, IQRs: 31–59) years) were identified: 16 were initially supported with VA-ECMO and 16 with VV-ECMO. The median time to V-AV conversion was 2 (1–5) days. After V-AV implantation, heart rate and norepinephrine dose significantly decreased, while PaO2 and SaO2 significantly increased compared to baseline values. Lactate levels significantly decreased from 3.9 (2.3–7.1) to 2.8 (1.4–4.4) mmol/L (p = 0.048). A significant increase in the overall ECMO blood flow (from 4.5 (3.8–5.0) to 4.9 (4.3–5.9) L/min; p < 0.01) was observed, with 3.0 (2.5–3.2) L/min for the arterial and 2.8 (2.1–3.6) L/min for the venous return flows. Conclusions: In ECMO patients with differential hypoxia or persistently low cardiac output syndrome, V-AV conversion was associated with improvement in some hemodynamic and respiratory parameters. A significant increase in the overall ECMO blood flow was also observed, with similar flow distributed into the arterial and venous return cannulas.