IFN-regulatory factor-1 (IRF-1) is a transcription factor that regulates the expression of IFN-induced genes and type I IFN. It has previously been demonstrated that IRF-1-deficient mice show reduced susceptibility to experimental autoimmune encephalomyelitis (EAE) induced by a peptide from myelin basic protein. To further study the role of IRF-1 in brain inflammation, we analyzed EAE induced by immunization with a myelin oligodendrocyte glycoprotein-derived peptide in 129/Sv mice lacking IRF-1. We found that these mice were almost completely resistant to EAE induction and that this unresponsiveness was intrinsically related to the IRF-1 deficiency of the T cells, but not with any other cell type. Furthermore, we show that the amelioration of EAE was associated with increased production of T(h)2-type and decreased production of T(h)1-type cytokines. These results demonstrate that absence of IRF-1 in myelin-specific T cells results in protection from severe EAE and is associated with a skewing of the T cell response towards T(h)2.