The ability of cyclosporine to prevent the increase in Ia and H-2K expression that occurs in mice with graft-vs-host disease (GVHD) was examined by means of absorption, indirect immunofluorescent staining (IIF), and indirect immunoperoxidase staining (IIP). Acute GVHD was induced in irradiated C3H/HeJ mice (H-2k) by injections of bone marrow and spleen cells from C57BL/6J mice (H-2b). Ten days after induction of acute GVHD, the spleens of mice not receiving cyclosporine expressed only donor Ia, reflecting their reconstitution by donor cells. The kidneys of such mice had a 10-fold increase in host Ia and H-2K expression, as previously reported. Treatment with cyclosporine reduced the amount of donor Ia and H-2K in spleens, and prevented the enhanced expression of recipient Ia and H-2K in kidneys in a dose-dependent manner. IIF or IIP staining showed that the principal change was in kidney tubules, where the induction of Ia and H-2K expression was greatly diminished. Cyclosporine administered to normal mice did not alter Ia expression except at high doses, at which it decreased Ia expression in kidneys and in spleens. The results suggest that prevention of enhanced MHC product expression could be part of the immunosuppressive actions of cyclosporine.