The nature of the autoimmune T cell response to myelin oligodendrocyte glycoprotein (MOG), recently recognized as a potential target antigen in multiple sclerosis (MS), has not yet been characterized, in contrast to the T cell reactivity to other potential target antigens in MS such as myelin basic protein and proteolipid protein. Here, we show that the encephalitogenicity of the recombinant Ig‐like domain of human MOG is associated, in H‐2^b mice, with an immunodominant T cell reactivity against a single region of MOG spanning amino acids 35–55, accounting for the previously reported strong encephalitogenic activity of pMOG 35–55. A single injection of pMOG 35–55 with or without administration of pertussis toxin was sufficient to induce severe clinical experimental autoimmune encephalomyelitis (EAE) in H‐2^b mice. Encephalitogenic pMOG 35–55‐specific T cell lines derived from C3H.SW (Vβ^b) mice were diverse in their TCR Vβ gene usage (Vβ1, Vβ6, Vβ8 and Vβ15), although Vβ8.2 was most predominantly expressed (48%). However, Vβ8⁺ T cells may only be part of the encephalitogenic MOG‐specific T cell repertoire in H‐2^b mice, as demonstrated by the susceptibility of C57L (Vβ^a) mice to disease induced by pMOG 35–55. Encephalitogenic T cell lines from Vβ^a mice were also diverse in their TCR Vβ gene usage (Vβ1, Vβ2, Vβ6, Vβ14 and Vβ16). Such a heterogeneous TCR Vβ gene expression by pMOG 35–55/I‐A^b‐reactive T cells from both Vβ^a and Vβ^b H‐2^b mice suggested multiple epitopes within pMOG 35–55. Analysis of the pattern of reactivity by pMOG 35–55‐reactive T cells to a set of truncated peptides was not commensurate with independent nested epitopes, but revealed a requirement for recognition of a core sequence, YRSPFSRVV (pMOG 40–48). However, optimal stimulation was obtained with longer peptides, with each additional amino acid flanking either the N or the C terminus differentially increasing the stimulatory capacity of pMOG 40–48. Nonetheless, pMOG 40–48 was the minimal encephalitogenic epitope for both Vβ^a and Vβ^b mice. Thus, the T cell reactivity against the immunodominant encephalitogenic region of MOG is characterized by a diverse Vβ gene usage and a requirement for the same core epitope. This pattern of reactivity may favor epitope‐directed, rather than TCR‐targeted, approaches to immunospecific therapy for MOG‐related autoimmune disease.