OBJECTIVE To assess the efficacy and side effects of tacrolimus, a potent immunosuppressive macrolide antibiotic, in the treatment of sight-threatening uveitis. METHODS A clinical study of tacrolimus in patients who required systemic immunosuppression for control of uveitis, but were refractory to cyclosporine. METHODS Six patients with uveitis were treated: three had Behçet disease, one had microscopic polyangiitis, one had pars planitis, and one had idiopathic retinal vasculitis. METHODS Patients with sight-threatening uveitis refractory to cyclosporine were treated with tacrolimus. METHODS Intraocular inflammation, visual acuity (VA), neovascularization. Adverse effects of tacrolimus were documented. RESULTS The posterior uveitis remained controlled in all patients while they were taking tacrolimus. Five of the six patients showed improvement, defined as improvement of two or more lines of Snellen acuity or a decrease in the binocular indirect ophthalmoscopy score (P < 0.05, Sign test). One patient with Behçet disease showed a marked improvement in best-corrected VA from 1/60 to 6/24. Two patients with Behçet disease showed a modest improvement in VA in the affected eye and had no disease activity in the other eye. The patient with microscopic polyangiitis was symptomatically improved, and there was no progression of the posterior uveitis. The patient with pars planitis had an improvement in VA from 6/18 to 6/9. The patient with retinal vasculitis showed partial regression of neovascularization on tacrolimus. Side effects were less troublesome than with cyclosporine. CONCLUSIONS Tacrolimus (FK506) has a useful role as an immunosuppressive agent for the treatment of sight-threatening uveitis in patients who did not respond to cyclosporine either because of lack of therapeutic effect or unacceptable adverse effects.