ECMO is used to provide cardiopulmonary support to critically ill patients, but the ability of the renin‐angiotensin‐aldosterone system to function appropriately during ECMO remains unclear. In this study, plasma renin activity (PRA) and aldosterone (ALDO) were compared at baseline and before and after stabilization on veno‐arterial ECMO for 2 hours in anesthetized piglets either during control (n=10) or endotoxin‐induced septic shock (n=9) states. In control piglets, ECMO was able to maintain mean arterial pressure (MAP) at baseline levels and PRA and ALDO remained unchanged. In contrast, endotoxin induced a 46% decrease (p<0.01) in MAP, and while ECMO could maintain flow at this decreased MAP, it did not return MAP to baseline. PRA appropriately increased in response to shock, but ultimately dropped by 54% (p<0.01) in early ECMO. ALDO increased in response to shock, and remained constant during ECMO. There was a strong correlation between PRA and ALDO at baseline (r=0.90, p<0.01) and on ECMO in control piglets (r= 0.70, p<0.01), but septic shock disrupted that relationship. Plasma sodium concentrations increased (p<0.01) from 137 ± 3.3 to 145 ± 0.7 mEq/L in shock, and with sustained ALDO, remained at this elevated level throughout ECMO. Results suggest that ALDO sodium regulating ability remains intact during ECMO but PRA is attenuated during ECMO in the endotoxic shock state.