Experimental Allergic Encephalomyelitis (EAE) is a neuroinflammatory, autoimmune disorder in which myelin-reactive Th1 T cells with a restricted TCRVbeta repertoire play a pathogenic role. Here, I show that an engineered single-chain TCR containing dominant TCRValpha/Vbeta encephalitogenic elements, when administered in aluminum adjuvant, generates a marked anti-TCR humoral response that correlated with protection against the development of EAE in Vbeta8-expressing B10.PL but not in Vbeta8-deficient SJL mice. sc-TCR/Al vaccination was highly efficient in preventing murine EAE in a TCR-specific manner through a mechanism involving anti-TCR B cells and/or antibodies. Collectively, these data have important implications for designing preventive or therapeutic strategies combining TCR vaccination with the use of aluminum adjuvant in the treatment of multiple sclerosis and other human autoimmune inflammatory diseases.