OBJECTIVE To determine whether anterior chamber-associated immune deviation (ACAID) promotes corneal allograft survival. METHODS CB6F1 mice were grafted with orthotopic corneal transplants from C3H donors (mismatch at the entire major histocompatibility complex plus multiple minor histocompatibility loci) and from NZB donors (mismatch only at multiple minor histocompatibility loci). ACAID was induced by priming in the anterior chamber (AC) with either Ia- spleen cells, Ia+ spleen cells, corneal endothelial cells, or corneal epithelial cells from corneal allograft donors before orthotopic transplantation. The role of ACAID in promoting corneal allograft survival was examined by determining the fate of corneal allografts in splenectomized and eusplenic mice. RESULTS Anterior chamber priming produced a modest enhancement of the survival of fully allogeneic C3H corneal allografts. By contrast, AC priming with Ia- NZB spleen cells or NZB corneal endothelial cells results in the permanent acceptance of NZB corneal grafts in 60% and 90% of the CB6F1 hosts, respectively. Abolition of ACAID by splenectomy resulted in a sharp increase in the incidence of graft rejection in donor-host combinations involving multiple minor histocompatibility disparity. CONCLUSIONS Anterior chamber priming with alloantigens promotes corneal allograft survival in nonimmune and preimmune hosts. Disruption of the camero-splenic axis prevents the induction of ACAID and greatly increases the risk for corneal allograft rejection.