UNLABELLED: Improved microsurgical techniques and better immunosuppressive treatment have led to an increase in the number of corneal transplantations. However, graft rejection due to a disparity between donor and recipient major histocompatibility antigens remains the major complication. The risk of graft rejection is further increased in patients with vascularized graft beds and in presensitized persons. Well-designed experimental studies and clinical experience have clearly shown the importance of class-I-antigens. However, class-II antigens have not yet been studied to the same extent. METHODS: Multiorgan donors and corneal graft recipients were HLA typed using the lymphocytotoxicity test previously described by Terasaki. The recipients were typed retrospectively. Cadaver corneal graft donors were typed using a novel HLA typing technique on retinal pigment epithelial cells, as previously described by us. Postoperatively, all recipients were routinely examined for rejection over a period of 2 years. RESULTS: Graft rejection was observed in 25% of the 133 high-risk patients. Of the 13 class-I-typed patients who showed a rejection 9 persons had two or more major histocompatibility mismatches. Of the 12 patients without rejection problems only 5 had two or more HLA class-I-mismatches. Of the patients with one or two matches at the HLA-DR locus there were only 4 out of 9 patients with at least one graft rejection; 5 out of 6 patients showed no signs of rejection. CONCLUSIONS: Mismatches at either class-I- or class-II- gene loci lead to a higher frequency in corneal graft rejection. Apart from the major histocompatibility mismatches, other factors also influence graft rejection, such as the distance between the corneal transplant and corneal vessels, presensitization, and the indication for corneal grafting. If we are to define the factors influencing graft rejection better and further increase our knowledge on the role the major histocompatibility antigens play in corneal graft rejection in a larger patient group, then cooperation with other transplantation centers will be required.