We compared the distribution of HLA-ABC (class I) and HLA-DR (class II) antigens on fresh human donor corneal tissue, donor corneas following a 72-hour storage in McCarey-Kaufman (M-K) medium, and corneal buttons from patients with allograft rejection and with chronic herpetic stromal keratitis. Incubation in M-K media had little or no effect on the distribution of HLA antigens as compared with fresh tissue. In contrast to control corneas, both HLA class I and II antigens were detected on corneal endothelial cells, cells in the stroma, and on basal epithelial cells in rejected allografts. Corneal endothelium in herpetic buttons did not express detectable HLA antigens. HLA-DR positive Langerhan's cells were demonstrated in the central corneal epithelium of rejected allografts, as well as in herpetic corneas, but not in control corneas except at the limbus. Based upon these observations, a theory of corneal allograft rejection in humans is proposed based upon the induction of class I HLA-ABC and class II HLA-DR antigens on cells in the donor button by a factor(s) associated with cellular inflammation.