We used immunohistologic techniques with a penetrating keratoplasty model in the rat to study the mechanisms of corneal transplant rejection. Thirteen of 14 syngeneic grafts remained clear in contrast to 24 of 26 allogeneic grafts, which had a rejection reaction. Immunohistochemical studies of syngeneic grafts showed only rare inflammatory cells in the central grafts; however, a focal inflammatory reaction made up of macrophages and T-helper/inducer lymphocytes was seen surrounding the sutures and in the wound. In contrast, immunohistochemical studies of allogeneic grafts showed diffuse inflammation throughout the donor and recipient corneas with T-suppressor/cytotoxic cells, T-helper/inducer cells, and macrophages, resulting in destruction of the donor endothelium, neovascularization, and graft failure. Class II antigen expression was seen extensively on Langerhans cells, donor keratocytes, and both the donor and recipient endothelial cells. These findings emphasize the role of early nonspecific inflammation in the wound and around the sutures, and delineate the cellular immune response and class II antigen expression in corneal allograft rejection.