Extracorporeal liver cross-circulation (ELC) using genetically modified pig livers may address an unmet need for temporary liver support in patients with acute or acute-on-chronic liver failure. This study used the ELC platform to evaluate early immune responses and assess xenogeneic liver physiological support in a human decedent model. Four human decedents underwent ELC using pig livers with a triple glycan knockout; insertion of seven human transgenes and inactivation of pig endogenous retroviruses. Intravenous methylprednisolone was administered for immunosuppression. In the case of decedents 1-3, ELC was performed for 72-84 h with the native livers of the decedents remaining in situ. In the case of decedent 4, hepatectomy was performed, followed by 48 h of xenogeneic liver support exclusively using ELC. Biopsies of xenogeneic livers demonstrated preserved parenchymal architecture, mild immune infiltration and IgM deposition. Xenogeneic livers produced bile and supplemented native hepatocellular function. In decedent 4, xenogeneic liver-only support after hepatectomy maintained hemodynamic stability, normal pH, lactate, ammonia, international normalized ratio and sustained metabolic function. This study shows that ELC is feasible using xenogeneic livers with minimal immunosuppression and can provide effective liver support.