PURPOSE: To evaluate the long-term efficacy and side effects of off-label topical tacrolimus 0.03% ointment (Protopic; Fujisawa Health, Deerfield, IL) as a sole second-line immunosuppressive agent in the management of high-risk corneal grafts. METHODS: Four consecutive patients underwent high-risk penetrating keratoplasty (4 grafts) with a prior diagnosis of corneal scar secondary to herpetic keratitis, keratoconus, acanthamoeba keratitis, and Fuchs endothelial dystrophy, respectively. All 4 patients developed steroid-induced glaucoma and failed traditional immunosuppressant therapy. Patients were started on topical tacrolimus ointment 0.03%, twice daily, which was tapered to the lowest possible therapeutic dose that maintained its antirejection efficacy. Patients were monitored for adverse treatment effects. The mean follow-up was 33 months (range, 26-48 months), and the mean treatment duration was 22.6 months (range, 13-32 months). RESULTS: All 4 high-risk corneal transplant patients experienced episodes of acute rejection that was successfully reversed with topical tacrolimus treatment. During tacrolimus treatment, there were no further episodes of graft rejection and no incidents of herpes simplex virus infection or reactivation, with the longest follow-up being 4 years. Two patients have been successfully tapered off tacrolimus, and 2 patients are currently on once-daily dosing. No adverse effects were observed. CONCLUSIONS: Topical tacrolimus 0.03% ointment seems to be a promising second-line immunosuppressant in management of high-risk grafts.