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Acute kidney injury (AKI) is a common clinical disorder and one of the major causes of morbidity and mortality in the postoperative period. In this study, the safety and efficacy of autologous mitochondrial transplantation by intra-arterial injection for renal protection in a swine model of bilateral renal ischemia-reperfusion injury (IRI) was investigated. Female Yorkshire pigs underwent percutaneous bilateral temporary occlusion of the renal arteries with balloon-catheters. Following 60 minutes ischemia, the balloon catheters were deflated and the animals received either autologous mitochondria suspended in vehicle or vehicle alone, delivered as a single bolus to the renal arteries. The injected mitochondria were rapidly taken up by the kidney and were distributed throughout the tubular epithelium of cortex and medulla. There were no safety related issues detected with mitochondrial transplantation. Following 24 hours of reperfusion, estimated glomerular filtration rate and urine output were significantly increased while serum creatinine and blood urea nitrogen were significantly decreased in swine receiving mitochondria as compared to those receiving vehicle. Gross anatomy, histopathological analysis, acute tubular necrosis scoring and transmission electron microscopy showed that the renal cortex of vehicle group had extensive coagulative necrosis of primarily proximal tubules, while the mitochondrial transplanted kidney showed only patchy mild acute tubular injury. Renal cortex IL-6 expression was significantly increased in Vehicle kidneys as compared to the kidneys receiving mitochondrial transplantation. These results demonstrate that mitochondrial transplantation by intra-arterial injection provides renal protection from IRI, significantly enhancing renal function and reducing renal damage.