This is the case report of a 13 year old Quarter Horse mare who presented for severe neurologic signs including laryngeal paralysis, obtundation, left-sided facial paralysis, right-sided head tilt, and ataxia. CSF analysis, necropsy, histopathology, rabies and arbovirus assays were performed with a resulting diagnosis of west nile virus (WNV). This case is an atypical presentation of WNV in that more of the signs are localized to the cerebral cortex and brainstem. WNV pathogenesis and specifically neuropathogenesis are of interest to researchers since many horses exposed to the virus do not succumb to neurologic disease. Analyzing the systemic conditions that lead to virus entry into the central nervous system as well as the role of the blood brain barrier and immune system in the neuropathogenesis of WNV are discussed in this report. The variability in the neuroanatomic localization of lesions and severity of the neurologic deficits suggests neuropathogenesis varies in the individual.