Cells in the brain express unusually low levels of antigens encoded by the major histocompatibility complex (MHC). This is somewhat surprising as class I (H-2) and class II (Ia) MHC antigens have critical roles in immune responses. The activation of T lymphocytes is associated with the enhanced expression of these antigens and this effect is mediated by a specific T-cell lymphokine, gamma-interferon (IFN-gamma). Here we show that IFN-gamma induces a dramatic increase in the expression of H-2 antigens on the cells of the brain. After exposure to IFN-gamma in vitro, all surviving cells, including most astrocytes, oligodendrocytes, microglia and at least some neurones, express H-2 antigens. Direct injection of IFN-gamma into the brains of mice indicated that H-2 antigens were also induced in vivo. Furthermore, IFN-gamma induced Ia antigens on a subpopulation of astrocytes. The induction of H-2 antigens by IFN-gamma may render brain cells competent to initiate and participate in immune reactions and may therefore contribute to both immunoprotective and immunopathological responses in the brain.