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Multiple sclerosis seems to be an autoimmune disease of unknown aetiology affecting the white matter of the CNS. It is generally accepted that the autoimmune response is directed against specific components of myelin. We show here that proteasome, a ubiquitous protease complex composed of 14 different subunits, is a target for autoantibodies (IgG and IgM classes) present in the serum (66%, 73 out of 110) and in the CSF (61%, 16 out of 26) of patients with multiple sclerosis. Using recombinant proteasomal subunits we demonstrate the presence of specific autoantibodies against subunits C2, C8, C9 and C5 in multiple sclerosis patients. Recombinant C2 constructs allow us to localize an immunodominant autoepitope recognized by the sera of multiple sclerosis patients within the C-terminal of C2 proteasomal subunit (251-DEPAEKADEPMEH-263). In addition, two constructs of the recombinant proteasomal subunits C2 and C8 were also used to study the proliferation of peripheral blood mononuclear cells from multiple sclerosis patients; 12 out of 30 (40%) multiple sclerosis patients show positive proliferation with one or both of these recombinant subunits. The high prevalence of anti-proteasome autoantibodies in multiple sclerosis sera compared with sera from patients with other chronic inflammatory conditions: systemic lupus erythematosus (35%, 35 out of 100), primary Sjogren's syndrome (16%, 5 out of 31), vasculitis (0 out of 20), sarcoidosis (7%, 1 out of 13) and Behcet's disease (19%, 4 out of 21) suggest that humoral autoreactivity to proteasome could be a useful test in multiple sclerosis patients that may be of help in the diagnosis and/or progression of this chronic inflammatory disease. Finally, these results suggest that some global abnormality in B and/or T cell function is also involved in the chronic inflammatory response observed in multiple sclerosis patients, as it is frequently observed in other human organ-specific autoimmune diseases.