Neuropathological examination of three males with cerebro-hepato-renal (Zellweger) syndrome (CHRS) revealed selective neuronal lipidosis and neuroaxonal dystrophy of the dorsal nucleus of Clarke and lateral cuneate nucleus. This lipidotic alteration was visualized as perikaryal or axonal enlargements with cytoplasmic striations. With the light microscope, the striated material was birefringent and resistant to traditional lipid stains; ultrastructurally, it was composed of lipid clefts, lamellae and lamellar-lipid profiles; biochemically, the affected region contained large amounts of cholesterol esterified to very long-chain fatty acids, both saturated and monounsaturated. This metabolic lesion, though localized to specific sensory neurons, suggests that a more generalized defect in neuronal fatty acid metabolism may be operative in CHRS.