The detection of raised immunoglobulin and the presence of oligoclonal bands (OCBs) on electrophoresis of multiple sclerosis (MS) CSF has been a useful diagnostic test, but a universal antigen to which these MS antibodies are directed has yet to be found. Potentially immunogenic heat shock proteins (HSPs) are preferential expressed in vitro in human oligodendrocytes compared with other glia, and in situ in oligodendrocytes found within the plaques of MS. Immunoreactivity directed against HSPs might therefore contribute to the immune-mediated demyelinating process found in MS. We examined this possibility by quantitatively (ELISA) measuring antibodies directed against a recombinant human HSP (HSP60) in CSF from 18 MS patients, and compared them with eight patients with acute disseminated encephalomyelitis, 12 with demyelinating peripheral neuropathies, and 59 with other neurologic diseases. Immunoblotting was used to confirm the specificity of the antibodies for binding to HSP60. We found a statistically significant correlation between antibody titers to HSP60 and the presence of OCBs in CSF. These results support the notion that HSP expression in the CNS, such as that observed in MS, may be immunogenic, leading to localized HSP antibody secretion. Such HSP-directed immunoreactivity could play a role in the pathogenesis of MS and other immune-mediated disorders of the nervous system.