Leflunomide (LEF) is a novel immunomodulator which has been reported to be efficacious in experimental models of systemic autoimmune diseases and in treating rheumatoid arthritis in man. Leflunomide's ability to ameliorate ocular disease processes was investigated in a model of autoimmune eye disease, experimental autoimmune uveitis (EAU). EAU was induced by the injection of retinal S-antigen (S-Ag) into the foot-pad of Lewis rats. Leflunomide, or the reference compound cyclosporin A (CSA), was administered orally or topically (to one eye) each day beginning on the day of S-Ag injection. Drug efficacy was measured by the suppression in clinical signs of ocular inflammation and confirmed by histology. Both oral and topical ocular treatment with LEF suppressed the ocular disease signs and symptoms and retinal necrosis and reduced the S-Ag antibody levels associated with EAU in a dose-dependent manner. Both LEF and CSA were able to inhibit totally the disease manifestations of EAU; however, a comparison of the IC50 and IC90 values indicate that LEF is more potent than CSA in inhibiting EAU. These results suggest that leflunomide may be useful for treating autoimmune diseases of the eye.