We wanted to find evidence of antibody to myelin basic protein (MBP) in patients with MS by detecting their shared usage of immunoglobulin genes. As demonstrated by the idiotopes (Id) of murine monoclonal antibody to peptides of MBP, there is limited use of the variable (V) region immunoglobulin genes for the immune response in mice to this encephalitogenic protein. Cross- reactive Ids have been detected across different murine strains and shared by T and B cells. One cross-reactive Id, designated as 845D3 Id, is located on the V region of κ light chains of two murine monoclonal antibodies, one to MBP peptide 80-89 and the other to MBP peptide acetyl 1-9. To examine the occurrence of 845D3 Id in MS, we used the V region of a light chain (V(L) of one of the monoclonal antibodies to probe the V(L) genes expressed in B cells in CSF of 50 patients (31 MS and 19 non-MS). The V(L) genes expressed in B cells found in CSF were amplified by polymerase chain reaction using universal human V-region primers. The 845D3 Id probe detected the Id+ V region in the CSF of 14 of 31 MS patients, 1 of 9 patients with other neurologic diseases, and 1 of 10 non-neurologic patients. The gene product was more common in but not restricted to CSF with oligoclonal bands. The presence in CSF of MS patients of a cross-reactive Id to different MBP peptides is indicative of an immune response to this encephalitogenic myelin protein in a segment of MS patients. These findings are also evidence for limited usage of V-region Ig genes in the immune response of humans to MBP and the possible importance of an Id network for MBP in demyelinating disease.