Cuprizone (biscyclohexanone oxaldihydrazone) was neurotoxic when fed to rats and guinea pigs and produced spongy degeneration of the white and gray matter of various parts of the brain. Signs of neurologic disturbances and hydrocephalus did not occur. The lesions were more severe in the rat and sites of predilection included areas of the telencephalon, including the neocortex in guinea pigs, thalmic nuclei, medial geniculate body, caudal colliculi, and cerebellum. Most severe and consistent changes were present in the rat, and were found in the white matter around the cerebellar nuclei. The basis alteration was edema creating, when severe, a status spongiosus. The vacuolar changes were accompanied by glial hypertrophy and demyelination in rats, but no reactive astroglia were observed in guinea pigs.