A crucial question in the study of tumor neuro-immunology concerns the capacity of the central nervous system to initiate and execute an immune response. In a 100% fatal rat malignant glioma model, genetically modified tumors secreting INF-γ intracerebrally generate an immune response resulting in a substantial increase in survival time, tumor rejection and specific systemic immunity. Tumors modified to secrete IL-2 alone do not change the biologic behavior of transfected gliomas. INF-γ induces elevated expression of major-histocompatibility-complex-class-I and -class-II molecules in microglia throughout the brain and invokes enhanced tumor infiltration by CD4, CD8 and NK cells. These findings demonstrate successful immunization against a central-nervous-system tumor by direct priming in the brain with a live growth-competent tumor vaccine.