Although there is increasing awareness of adverse effects associated with use of the high-fat ketogenic diet, very little is known regarding its long-term clinical consequences, especially in relation to cardiovascular health. Recent reports have highlighted rare but significant cardiac problems in patients treated with the ketogenic diet. Given the inherent limitations in conducting detailed pathologic assessments in patients, we asked whether histologic changes might develop in the brain and skeletal muscle of mice fed a high-fat diet for 2 to 3 months. We found no evidence of gross morphologic or histochemical alterations in muscle or brain after administration of the ketogenic diet. Further, there was no abnormal lipid storage or mitochondrial enzymatic staining. Our data suggest that patients chronically treated with a ketogenic diet are not likely to develop a lipid myopathy or neuronal inclusions.