Tacrolimus and rapamycin both belong to a new family of immunosuppressants, immunophilin ligands, but the mechanisms by which they inhibit T cell activation are different. Therefore, we tested the immunosuppressive effects of combination therapy with low doses of tacrolimus and rapamycin on experimental autoimmune uveoretinitis (EAU) in rats. Male Lewis rats, immunized with S-antigen (S-Ag) were given intraperitoneal injection of the combined drugs for 14 days after the immunization with S-Ag. Effects were evaluated by clinical observations, histological examination and immune response. The combination therapy with tacrolimus (0.1 mg/kg per day) and rapamycin (0.03 mg/kg per day) achieved 100% suppression of clinical EAU and 66.7% suppression of histological EAU; tacrolimus combined with a higher dose of rapamycin (0.1 mg/kg per day) caused 100% suppression clinically and histologically. Therapy with either drug alone achieved only partial suppression: tacrolimus alone (0.1 or 0.2 mg/kg per day) or rapamycin alone (0.03-0.2 mg/kg per day). Doubling the dose of either drug produced only 16.7% suppression with rapamycin or 50% suppression with tacrolimus. The serum antibody levels to S-Ag and proliferative response of lymphocytes to S-Ag were also significantly suppressed by the combination therapy with low doses of tacrolimus and rapamycin.