OBJECTIVE Recurrence of herpetic keratitis and immune reactions is the major cause of graft failures after penetrating keratoplasty as a consequence of herpes simplex keratitis. No treatment regimen is yet considered a standard of care. This retrospective study analyzes the effectiveness of combined systemic acyclovir and immunosuppressive therapy with cyclosporine A (CSA) or mycophenolate mofetil (MMF) after high-risk keratoplasty in herpetic keratitis. METHODS A total of 87 high-risk keratoplasties treated with postoperative combined systemic acyclovir and immunosuppressive therapy with CSA or MMF were analyzed retrospectively according to the therapeutic regimen, the degree of preoperative corneal vascularization, and tissue matching of the graft. Endpoints included immunological graft rejection, recurrence of the herpetic keratitis, graft failure, and visual acuity. RESULTS There was an overall trend toward an improvement of visual acuity. Graft failure occurred in 13.1%, in all cases after termination of immunosuppression with MMF or CSA. In 4 of 11 cases, immune reactions caused graft failure. Patients with 3 to 4 quadrants of corneal vascularization showed significantly higher rates of graft rejection than patients with 1 to 2 quadrants vascularized or avascular corneas. Herpetic recurrence occurred in 31.8% and caused 18.2% of graft failure. In 7 of 23 cases, graft rejection was induced by herpetic recurrence. CONCLUSIONS Graft survival rate and functional outcome after postoperative antiviral and immunosuppressive treatment in cases of penetrating keratoplasties after herpetic keratitis are comparable with results of normal-risk keratoplasties, despite existing high risks for immune rejections or herpetic recurrences.