• Lipid and fatty acid composition of myelin and synaptosomes isolated from brains of phenylketonuric (PKU) and Down syndrome (DS) patients and patients with neither of these disorders was determined. No differences were observed in the proportions of cholesterol to phospholipids in synaptosomes and cholesterol to galactolipids to phospholipids in myelin or in the fatty acid composition of phospholipids in synaptosomes. However, the myelin from PKU brains contained reduced proportions of unsaturated and long-chain fatty acids. We conclude that genetic PKU and its experimental model have in common a defect in cerebral fatty acid metabolism, and that cerebral lipid abnormalities in this condition, rather than being generalized, may be confined to the glial cell population that synthesizes myelin. We further conclude that DS is not associated with an abnormality of cerebral lipid metabolism.