The brain has long been considered to be an immunologically privileged site. However, privilege is not absolute, as has been shown by the inability of foreign tissue grafts to survive indefinitely in the brain. The rejection of this tissue is accompanied by the upregulation of major histocompatibility complex (MHC) antigen expression. Therefore it is essential to define conditions that influence the expression of these antigens in the brain, especially since such a definition may further the understanding of disease processes that lead to the autoimmune destruction of the central nervous system. Here we show that both MHC class I and class II antigens are expressed within 1 or 2 days of eye removal by cells showing the morphological characteristics of microglia. Expression is seen along the optic pathway and within the brainstem centers to which optic axons project. In the early stages of the reaction, MHC class I antigen expression is seen throughout the optic pathway, including the terminal distribution areas of the subcortical visual centers, while MHC cells class II are localised mainly to degenerating myelinated fiber systems. These changes are not accompanied by any alteration in the integrity of the blood-brain barrier. During the second week postlesion, class I positive cells are found beyond the confines of the degenerating pathways, while class II positive cells are seen within regions such as the stratum griseum superficiale of the superior colliculus, where few myelinated axons are present. There is subsequent diminution of MHC positive cells, but a small number of cells are still seen 60 days post-lesion. Focal lesions within the eye show that at early survival times, while class I MHC positive cells are distributed throughout the nerve, class II positive cells are largely absent from the unmyelinated segment of the nerve. Retrograde changes in the retina after nerve section are accompanied only by MHC class I antigen expression. These observations show that neural degeneration is accompanied by a rigid sequence of events involving expression of MHC antigens by microglia. If foreign antigens were present in the brain while these events were taking place, it is possible that such antigens would be recognised and destroyed by the host immune system.