A mouse model of western equine encephalitis (WEE) was characterized for use in antiviral studies. Virus was detected in several tissues, most notably an average titer of 9.5 ± 1.1 log10 50% cell culture infectious doses (CCID50)/g tissue in the brains of infected animals. Signs of WEE included limb weakness, paralysis, involuntary spasms or extension of limbs, clenching of paws, hunching, ruffling of fur, and eye exudates, many of which are indicative of neurological disease. The pyrazinecarboxamide derivative, T-705, was found to be active in Vero cells against WEE virus (WEEV) with an 90% effective concentration (EC90) of 49 μg/ml (selective index [SI] > 20). Treatment with T-705 in this WEE mouse model resulted in significant improvement in survival and mean day to death after oral treatment administered twice a day for 7 days at a dose of 400 mg/(kg d). Virus titer in the brain was not significantly reduced, despite a 1-log reduction in average brain titer in treated animals on 4 dpi. Signs of disease were relatively mild in treated animals, but were not eliminated. Treatment with T-705 improved morbidity and mortality of WEEV-infected mice, further illustrating the broad-spectrum activity of T-705 in the treatment of RNA viruses.