Induction of mild ketosis from caloric restriction or the ketogenic diet confers neuroprotection against a wide range of pathologies. Interestingly, the brain's ability to use exogenous ketone bodies for fuel has not been exploited therapeutically. We hypothesized that exogenous ketones would prevent hyperbaric oxygen-induced seizures in rats. Results demonstrate that intragastric administration of ketone ester in rats (n = 12) confers protection from CNS oxygen toxicity (5 ATA O₂) by delaying the latency to seizure from 16.4 ± 5 minutes (control) to 79.3 ± 11.7 minutes (10 g/kg ketone ester). In studies of primary cultured cortex neurons, fluorescence microscopy with dihydroethidium confirmed that superoxide anion production (measured as DHE fluorescence units) decreased significantly with ketone treatment (2 mM b-hydroxybutyrate). Superoxide anion production was 27% lower in hyperoxia-treated cultures. We conclude that oral administration of ketone ester is neuroprotective against seizures resulting from CNS oxygen toxicity in rats and that supplemental ketones reduce superoxide production in cultured cortex neurons exposed to hyperbaric oxygen. These observations support the anticonvulsant and neuroprotective effect of ketones for CNS oxygen toxicity.