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(1) Background: Fluid resuscitation is a necessary part of therapeutic measures to maintain sufficient hemodynamics in extracorporeal membrane oxygenation (ECMO) circulation. In a post-hoc analysis, we aimed to investigate the impact of increased volume therapy in veno-arterial ECMO circulation on renal function and organ edema in a large animal model. (2) Methods: ECMO therapy was performed in 12 female pigs (Deutsche Landrasse × Pietrain) for 10 h with subsequent euthanasia. Applicable volume, in regard to the necessary maintenance of hemodynamics, was divided into moderate and extensive volume therapy (MVT/EVT) due to the double quantity of calculated physiologic urine output for the planned study period. Respiratory and hemodynamic data were measured continuously. Additionally, renal function and organ edema were assessed by blood and tissue samples. (3) Results: Four pigs received MVT, and eight pigs received EVT. After 10 h of ECMO circulation, no major differences were seen between the groups in regard to hemodynamic and respiratory data. The relative change in creatinine after 10 h of ECMO support was significantly higher in EVT (1.3 ± 0.3 MVT vs. 1.8 ± 0.5 EVT; p = 0.033). No major differences were evident for lung, heart, liver, and kidney samples in regard to organ edema in comparison of EVT and MVT. Bowel tissue showed a higher percentage of edema in EVT compared to MVT (77 ± 2% MVT vs. 80 ± 3% EVT; p = 0.049). (4) Conclusions: The presented data suggest potential deterioration of renal function and intestinal mucosa function by an increase in tissue edema due to volume overload in ECMO therapy. [ABSTRACT FROM AUTHOR]