Summary: Purpose: The ketogenic diet (KD) is a high-fat, low-carbohydratc and -protein diet that has been used to treat refractory seizures in children for more than 75 years. However, little is known about how the KD inhibits seizures or its el'fects on epilcptogcnesis. Several animal models of epilepsy have responded favorably to KD treatment, but the KD has not been studied in animals with a genetic predisposition to seizures. Here we studied the antiepileptogenic effect of the KD in EL mice, an animal model for human idiopathic epilepsy.M&ods: Young male EL mice (postnatal day 30) were randomly separated into two groups fed ad libitum with either the KD (treated, n = 21) or Agway chow (control, n = 19). The mice werc wcighcd and tested for seizures once per week for a total of 10 weeks. The effects of the KD on plasma levels of ketone bodies and glucose were analyzed at several time points throughout the study. Associative learning was compared between treated and control animals using a water maze.Results: KD treatment delayed seizure onset in young male EL mice by 1 month; however, seizure protection was transient, inasmuch as the treated and control mice experienced a similar number and intensity of seizures after 6 wccks on the diet. Plasma glucose levels and associativc learning were similar in the treated and control groups, but the plasma P-hydroxybutyrate levels were significantly highcr in mice on the KD. The level of ketosis, however, was not predictive of seizure protection in EL mice.Conclusion: The KD delayed seizure onset in EL mice, suggesting a transient protection against epileptogcnesis. The KD did not influence plasma glucose levels or learning. Therefore, the EL mousc may serve as a good model to study the antiepileptogenic mechanisms of the KD.