The ability to study the immediate, early events in the demyelinating process has been difficult on account of the lack of model systems that address this phase of lesion development. The vast majority of animal models used to study multiple sclerosis (MS) focuses on the later events of myelin destruction. To address this deficiency, we have modified the currently used Theiler's murine encephalomyelitis virus (TMEV)-induced model of demyelination to precisely identify the area where virus-induced demyelination first occurs. Following surgical exposure of the spinal cord, we directly injected TMEV into the spinal cord of female SJL/J mice. Characterization of the events in the spinal cord in the days following injection of virus support the use of this model to dissect the pathways triggered in the host in the early phases of demyelination. A complete understanding of the genesis of the sclerotic plaque may provide insights into enhanced treatment for patients with central nervous system (CNS) demyelination.