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To determine the effect of ocular administration of anti-CD154 monoclonal antibody on the survival of orthotopic murine corneal transplants.BALB/c mice were used as recipients of multiple minor H- and MHC-mismatched orthotopic corneal transplants. Recipient beds were either avascular (normal-risk) or neovascularized (high-risk) at the time of surgery. Mice were randomized to receive either anti-CD154 antibody or control immunoglobulin by subconjunctival injection. All grafts were evaluated for signs of rejection by slitlamp biomicroscopy until week 20–24 with the therapy tapered and discontinued after week 8 and week 12, respectively.In normal-risk transplantation, the 8-week survival rate improved from 30% in control mice to 90% in anti-CD154 treated mice (p = 0.0061). In high-risk transplantation, the survival rate of anti–CD154-treated mice was enhanced to 55% compared with 0% in control mice at week 8 (p = 0.0184); however, tapering and termination of anti-CD154 led to some loss in graft survival, with a survival rate of 56% in normal-risk recipients, and 22% in high-risk recipients by week 20. Anti-CD40L treated animals displayed lower grades of postoperative corneal neovascularization (p <0.05), in particular in normal-risk recipients.Local ocular administration of anti-CD154 is effective in the prevention of corneal allograft rejection in normal-risk recipients, and in delaying the incidence of rejection in high-risk recipients. Long-term graft survival may not be fully achieved following termination of the CD40-CD154 pathway blockade.