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Background and Purpose: Ketogenic diet (KD) improves seizure control in patients with drug-resistant forms of epilepsy; however, the mechanism of action remains poorly understood. Increased mitochondrial levels of glutathione (GSH) might contribute to a change in seizure susceptibility suggestive of possible anticonvulsant role for GSH. Our goals were to quantify changes of absolute GSH levels in the brain by in vivo MR spectroscopy and correlate that with degree of seizure control in patients on KD. Methods: Five cognitively normal adult patients with drug-resistant epilepsy were initially included and 2 completed the study. Each patient was evaluated by a neurologist and registered dietitian at baseline, 1, 3, and 6 months for seizure status and diet adherence. Each patient received a baseline short TE single-voxel water-suppressed point-resolved spectroscopy (PRESS) 1 H MRS in parieto/occipital grey matter and parietal white matter on a 3 Tesla General Electric magnet prior to starting the ketogenic diet and a follow-up stury at 6 months. Multiple metabolites, including GSH, were quantified using LCModel.Results: After being on ketogenic diet for 6 months, both patients (42-years-old male and 35-years-old female) demonstrated marked increases in absolute GSH level in both gray matter (0.1 to 1.4 and 0.1 to 0.7 IU) and white matter (0.65 to 1.5 and 0.8 to 2 IU), as well as 50% improvements in seizure duration and frequency. Other metabolites including ketone bodies, Acetone (Acn), Beta hydroxybutyrate (βHB), and acetoacetate (AcAC), did not demonstrate consistent changes. Conclusion: Markedly increased levels of GSH (7-fold and 14-fold) were observed in longitudinal prospective study of two adult patients with intractable epilepsy with 50% seizure improvement after initiation of ketogenic diets. This pilot study supports the possible anticonvulsant role of GSH in the brain.