Immunologic rejection is a significant cause of graft failure in high-risk keratoplasty, with rejection rates exceeding 70% without immunosuppressive therapy. Cyclosporine A (CsA) is emerging as a valuable adjunct to corticosteroids, the standard rejection prevention therapy. A literature review conducted in March 2024 through PubMed, Proquest, and Google Scholar utilized keywords (keratoplasty OR “high risk keratoplasty” OR “high risk corneal transplantation” OR “corneal transplantation”) AND (cyclosporine OR ciclosporin OR ciclosporine), covering studies from 2000 to 2024. The review included three randomized controlled trials, four retrospective cohort studies, and one retrospective case–control study, evaluating rejection-free graft survival rates and side effects associated with CsA therapy. Topical CsA significantly reduced rejection events compared to controls at 1 year follow-up (n = 215, 17.78% vs. 32.41%, risk ratios [RR] 0.55, 95% confidence interval [CI]: 0.34–0.92, P = 0.02, I2 = 31%, fixed effects), whereas systemic CsA showed no significant difference (n = 248, 19.33% vs. 24.81%, RR 0.66, 95% CI: 0.40–1.08, P = 0.10, I2 = 0%, fixed effects). No significant difference in graft survival rates was observed between the CsA and control groups. Systemic CsA was associated with systemic side effects, whereas topical CsA primarily caused ocular side effects. In summary, topical CsA significantly reduces rejection rates without substantial ocular or systemic side effects. © 2026 Oman Ophthalmic Society.