Irrespective of HLA matching, a far higher proportion of human corneal allografts placed orthotopically in avascular corneal graft beds are accepted indefinitely, compared to other types of solid tissue allografts. However, many more corneal grafts are rejected if they are transplanted onto neovascularized recipient eyes. Using a murine model of orthotopic corneal transplantation in which grafts were placed in normal eyes, we have reported previously that grafts bearing minor H antigens alone are more likely to be rejected (approximately 50%) than are grafts displaying only MHC alloantigens (< 20%). Moreover, recipients of MHC plus minor H incompatible corneal grafts developed delayed hypersensitivity (DH) directed solely at minor H antigens. These studies have now been extended to include corneal grafts placed in neovascularized recipient eyes. Neovascularization was induced by placing sutures in the central cornea of one eye of BALB/c mice. Two weeks later corneas from C57BL/10 donors were grafted into these eyes. Rejection reactions were first apparent within 7 days and all grafts were destroyed by 14 days. Donor-specific DH responses were examined by injecting irradiated donor antigen-bearing spleen cells into the ear pinna. To distinguish DH directed at MHC versus minor antigens, some graft recipients were ear-challenged with BALB.B cells (donor MHC only), while other received B10.D2 cells (donor minor H only). Intense ear-swelling responses were evoked by B10.D2 cells, but not by BALB.B cells. These findings indicate that, for orthotopic corneal allografts, minor H antigens offer a more formidable barrier to graft acceptance than do MHC-encoded antigens. We speculate that this unexpected outcome may reflect a reduced level of MHC expression on corneal tissue. Moreover since the cornea lacks bone marrow derived dendritic cells, allorecognition by recipient T cells must occur via the indirect pathway, and in this situation minor H antigens may compete favorably with MHC antigens for processing and presentation by recipient antigen-presenting cells.