Immunologic rejection is the main cause of corneal graft failure, especially in vascularized corneal beds. The purpose of this study was to investigate the effect of systemic Cyclosporine-A (CsA) on the survival of corneal allografts in heavily vascularized rabbit corneal beds, following alkali burn. Heavy corneal vascularization was induced in one eye of 20 rabbits by alkali burn. Forty-five days later, penetrating keratoplasty was performed in all the heavily vascularized corneas. Twenty-five mg/kg/day of CsA was intramuscularly administered to 10 rabbits for 30 days. The other 10 rabbits were treated with the solvent without CsA and were used as a matched control group. The results show a significant difference in corneal allograft survival between the two groups. All corneal grafts in the untreated group were intensely rejected and vascularized within 3 weeks. Nine of the 10 corneal transplants, in the CsA-treated group, remained transparent without signs of immunologic rejection for > 180 days. In one corneal transplant, minor signs of rejection occurred. We suggest that CsA, when given systemically, is a potent drug in the prevention of immunologic rejection in high-risk corneal transplantations, such as allografts, in heavily vascularized corneas following alkali burn.