T he mechanisms underlying the initiation of virus-induced autoimmune disease are not well understood. Theiler’s murine encephalomyelitis virus–induced demyelinating disease (TMEV-IDD), a mouse model of multiple sclerosis, is initiated by TMEV-specific CD4⁺ T cells targeting virally infected central nervous system–resident (CNS-resident) antigen-presenting cells (APCs), leading to chronic activation of myelin epitope–specific CD4⁺ T cells via epitope spreading. Here we show that F4/80⁺, I-A^s+, CD45⁺ macrophages/microglia isolated from the CNS of TMEV-infected SJL mice have the ability to endogenously process and present virus epitopes at both acute and chronic stages of the disease. Relevant to the initiation of virus-induced autoimmune disease, only CNS APCs isolated from TMEV-infected mice with preexisting myelin damage, not those isolated from naive mice or mice with acute disease, were able to endogenously present a variety of proteolipid protein epitopes to specific Th1 lines. These results offer a mechanism by which localized virus-induced, T cell–mediated inflammatory myelin destruction leads to the recruitment/activation of CNS-resident APCs that can process and present endogenous self epitopes to autoantigen-specific T cells, and thus provide a mechanistic basis by which epitope spreading occurs.