Viral infection of the central nervous system can lead to long-term neurologic defects, including increased risk for the development of epilepsy. We describe the development of the first mouse model of viral-induced epilepsy after intracerebral infection with Theiler's murine encephalomyelitis virus. Mice were monitored with long-term video-electroencephalogram at multiple time points after infection. Most mice exhibited short-term symptomatic seizures within 3 to 7 days of infection. This was followed by a distinct latent period in which no seizures were observed. Prolonged video-electroencephalogram recordings at 2, 4, and 7 months after the initial infection revealed that a significant proportion of the mice developed profound, spontaneous epileptic seizures. Neuropathologic examination revealed hippocampal sclerosis in animals with epilepsy. Theiler's murine encephalomyelitis virus-infected C57BL/6 mice represent a novel "hit-and-run" model to investigate mechanisms underlying viral-induced short-term symptomatic seizures, epileptogenesis, and epilepsy. Importantly, this model will also be useful to investigate novel therapies for the treatment and prevention of epilepsy.