Cytotoxic T cells (CTL) play a critical role in controlling viral infections. Infection of neonatal NFSIN mice with a high dose of Cas-Br-M murine leukemia virus, a neuropathogenic type C retrovirus, results in virus-induced neurologic disease and in their failure to generate a protective CTL response. Cas-Br-M-specific CTL are necessary in the protection of neonatal mice from Cas-Br-M-induced neurologic disease. Here we demonstrate that intramuscular inoculation of newborn mice with naked DNA expressing the full length Cas-Br-M genome induces a virus-specific CTL-mediated response. This CTL response is mediated by CD8+ T cells, is long lasting and, when transferred to susceptible neonatal recipients, protects them from Cas-induced neurologic disease. We also provide evidence that the intramuscular inoculation of neonates with plasmid DNA encoding only env sequences induces a dose-dependent CTL response in the absence of an anti-MuLV antibody response.