PURPOSE: To report long-term results in a case series of patients treated with systemic immune suppression for prevention of penetrating keratoplasty (PKP) graft rejection. DESIGN: Retrospective noncomparative chart review. PARTICIPANTS: Three patients presented with PKP graft failure. METHODS: Patients received oral prednisone, azathioprine and cyclosporine to prevent rejection of repeat corneal transplant. Patients received repeat PKP and graft outcome was reported. MAIN OUTCOME MEASURES: Visual acuity and graft survival were recorded. RESULTS: Mean age was 55 years, two male and one female. Mean follow-up period was 37 months (range 24-46). All three patients completed the treatment protocol with minimal adverse effects. All grafts remained clear over observational period. CONCLUSION: Our study suggests that systemic immune suppression with 2 or more agents may be helpful to prevent corneal graft rejection in high-risk patients.