ABSTRACT Despite extensive research, clinical advancements, and improved rehabilitation strategies, spinal cord injury (SCI) continues to be a significant cause of disability and mortality worldwide, and no pharmacologic therapy has demonstrated significant improvement effects in the neurological or functional recovery of individuals with SCI. Therefore, there is an urgent need for innovative therapies for improving neurorecovery after SCI. The scientific premise of this project builds upon accumulating evidence that diet-based therapies, such as the ketogenic diet (KD), offer effective neuroprotection against secondary injury cascades and improve forelimb motor function in a rat model of SCI. The KD is a high-fat, low-carbohydrate diet designed to mimic the metabolic and biochemical changes that occur during calorie restriction, specifically ketosis. Ketone bodies have been shown to exert neuroprotective effects by attenuating neuroinflammation and inhibiting apoptosis in the spinal cord. Because neuroinflammation and induction of apoptotic pathways lead to progressive degeneration in the spinal cord shortly after the injury, inhibition of these processes by ketone bodies may enhance neurological recovery after an SCI. Indeed, our recent pilot study showed for the first time that, compared with a standard hospital diet (SD), 5 weeks of KD improved upper extremity motor function in patients with acute SCI. In addition, levels of a neuroinflammatory blood protein, fibrinogen, were lower in the KD serum samples than in the SD serum samples, suggesting a KD may induce anti-inflammatory effects in part by reducing fibrinogen. The acute stage after SCI is also characterized by hyperglycemia, which is strongly associated with poor functional outcomes at discharge. In our pilot study, fasting serum glucose levels decreased by 24 mg/dl in the KD group but increased by 0.7 mg/dl in the SD group. These provocative findings have led us to our central hypothesis that SCI patients who consume a KD over the first 5 weeks (average hospital stay) after injury will have better neurological recovery, functional independence, and glycemic control than the SCI patients who consume an SD during this period. We will test this hypothesis in a randomized, controlled trial with two specific aims: 1) Determine if 5 weeks of KD vs. SD significantly improves motor and sensory function, functional independence, and glycemic control in patients with acute SCI, and 2) Quantify serum biomarkers that are responsible for improvements in neurological recovery and functional independence. Our findings will uncover the molecular mechanisms by which targeted nutritional strategies can promote neurorecovery shortly after SCI and may lead to a safe, effective, simple, and economical intervention that improves health outcomes after SCI.