The effects of two novel immunosuppressants, FK506 and 15-deoxyspergualin (15-DSG), on experimental autoimmune uveoretinitis (EAU) were evaluated in the rat. Rats were immunized with retinal soluble antigen (S-antigen) and treated with FK506 or 15-DSG, and the disease induction as well as the immune responses to the antigen were examined. The results were compared with animals treated with cyclosporine (CsA) which has been widely used to treat refractory uveitis in humans. A dose-response study showed that FK506 suppressed EAU induction at doses 10–30 times lower than CsA when given on days 0–14 postimmunization, while 15-DSG suppressed the disease development at doses very similar to CsA. As with CsA, FK506 suppressed EAU induction when given only in the induction phase (days 0–5 postimmunization) or in the effector phase (days 7–12), but at doses much lower than CsA. On the other hand, 15-DSG suppressed EAU only at toxic doses with these schedules. The antigen specific mitotic response of lymphocytes was markedly suppressed by the three agents, while the antigen specific antibodies in sera were suppressed by 15-DSG and FK506 but not by CsA at doses effective in suppressing the disease induction. More significant findings were uniquely prolonged immunosuppressive effects of FK506: EAU induction as well as the immune responses to S-antigen were suppressed long after the cessation of drug treatment.