We injected guinea pig optic nerves with serum from patients with MS or acute optic neuritis (ON), or normal subjects. Serum from 12 of 17 MS patients, 3 of 3 patients with ON, and 5 of 11 normal age- and sex-matched controls produced myelin vesiculation and demyelination 24 hours after injection. Nerves injected with demyelinating serum contained oligodendrocytes with pyknotic nuclei and edematous, rarefied cytoplasm. Nerves injected with serum that did not cause demyelination did not have these oligodendrocyte changes. Serum from normal subjects or patients with MS may induce in vivo demyelination in mammalian CNS.