Persistent tolerant infection of rats with borna disease virus (BDV) results in a central nervous system (CNS) disease characterized by behavioral abnormalities. These disorders occur without inflammation and widespread cytolysis in the CNS. Therefore, mechanisms other than virally induced destruction of brain cells may explain the CNS disturbance caused by BDV. Previously, we have shown that astrocytes in the CNS express tissue factor (TF). TF functions as the primary cellular initiator of the coagulation protease cascades, resulting in the generation of the protease thrombin. Proteases and their inhibitors play important roles in the development and physiology of the CNS, and altered protease activity has been implicated in the pathophysiology of various neurological diseases. Here, we present evidence that TF expression in the brain is markedly increased during persistent infection with BDV. Persistent infection of cultured astrocytes with BDV also increased TF expression as a result of both increased transcription of the TF gene and stabilization of TF mRNA. We speculate that increased TF expression within the brain parenchyma may lead to increased protease activity in the CNS and contribute to virus-mediated CNS functional impairment by affecting neural cell interactions.