To investigate the immunological background and the immunosuppressive effect of antileukocyte function associated antigen-1 (LFA-1) monoclonal antibody (mAb) and FK506 in concordant corneal xenotransplantation, orthotopic penetrating keratoplasty was performed using Lewis rats as donors and BALB/c mice as recipients. Anti-LFA-1 mAb or FK506 (3 mg/kg/day) or both these immunosuppressants were administered intraperitoneally from days 0 to 12, postoperatively. The average survival periods in the untreated control group, FK506-treated, anti-LFA-1 mAb-treated and the combined-treatment groups were 5.8 ± 0.8, 9.4 ± 4.0, 8.7 ± 5.0 and 67.7 ± 16.4 (mean ± SD) days, respectively. In the untreated control group, mouse IgG, IgM and C3 were expressed on the rat corneal grafts during the early postoperative phase, and flow cytometrical studies revealed high titers of xenoreactive IgG and IgM antibodies. Th1 cytokines were expressed on xenografted corneal beds. However, local expressions of IgM, C3, Th1 cytokines and serum xenoreactive antibodies of IgG and IgM were suppressed in animals treated with anti-LFA-1 mAb and FK506. These results indicate that treatment with anti-LFA-1 mAb in combination with FK506 synergistically suppresses concordant corneal xenogeneic humoral and cell-mediated immune reactions.