We have examined the expression of the major histocompatibility complex (MHC) antigens and related genes in scrapie-infected hamster brain. Both the class I and the class II MHC genes as well as the class II-associated invariant chain were found to have an increased brain expression after scrapie infection. The increased expression of the class I complex was immunohistochemically localized primarily to neurons, though some astrocytes contained much smaller amounts of the class I complex. While there is no detectable immune response to scrapie infection, the possibility that increased MHC expression affords some defense against the scrapie agent is discussed.