a-Lipoic acid (α-LA) is a neuroprotective metabolic antioxidant that has been shown to cross the blood brain barrier. We tested whether a-LA is capable to prevent MOG35–55-induced experimental autoimmune encephalomyelitis (EAE), an established model of multiple sclerosis (MS). Daily oral administration of a-LA, starting at the time of immunization, significantly prevented EAE progression as compared to control mice. This was associated with a reduction of CNS infiltrating T cells and macrophages as well as decreased demyelination. We then tested a-LA in a therapeutic protocol aimed at suppressing EAE after its onset. Intraperitoneal (i.p.), but not oral, administration of a-LA significantly prevented disease progression when compared to vehicle-treated controls. Similarly, we observed significant reduction of demyelination and inflammatory infiltration. This clinical effect was not due to an impairment of MOG35–55 recognition by encephalitogenic T cells. In contrast, MOG-specific T cells showed a decreased production of IFNγ and IL-4, suggesting an immunosuppressive activity on both Th1 and Th2 cytokines. In addition, a-LA inhibited the proteolytic activity of MMP2 and MMP9 only at very high doses. Our data indicate that a-LA can effectively interfere with the autoimmune reaction associated with EAE through mechanisms other than its antioxidant activity and supports further studies on the use of a-LA as a potential therapy for MS.