Cynomolgus macaques were exposed by aerosol to a virulent strain of western equine encephalitis virus (WEEV). Between 4 and 6 days after exposure, macaques had a significantly elevated temperature that lasted for 3-4 days. Clinical signs of encephalitis began as the body temperature decreased, and then they rapidly increased in severity. Cynomolgus macaques with clinical signs of encephalitis had elevated white cell counts in the blood caused mostly by increased numbers of segmented neutrophils and monocytes. Elevated serum glucose levels also correlated with the severity of the clinical signs of encephalitis. Three cynomolgus macaques died; immunohistochemical evidence of viral antigen was present in the brain and central nervous system (CNS). Microscopic analysis also revealed a marked lymphocytic infiltrate in the CNS. Cynomolgus macaques will serve as a useful model of aerosol exposure to WEEV for the evaluation of potential vaccine candidates.