Corneal transplantations may survive when transplanted orthotopically even in the presence of massive corneal neovascularization, while such grafts would be rejected in heterotopic locations. Experiments with murine tissues have shown that cultured corneal tissue as well as iris/ciliary body (I/CB) tissue produce immunosuppressive factors. This was not the case when traumatized corneas were tested. We therefore wondered whether the same difference could be observed when explants of normal or pathological human corneas or I/CB tissues were tested. Supernatant of cultured cornea and I/CB tissue was added to a mixed lymphocyte reaction (BALB/c responder and C57B1/6 stimulator cells) and thymidine incorporation was measured. Culture supernatants from normal corneas and corneas with bullous keratopathy achieved similar levels of MLR inhibition, which could not be blocked by addition of anti-transforming-growth factor-beta 2 antibody or indomethacin. The supernatant from cultured I/CB cells from normal eyes and from eyes containing a posterior segment melanoma did not differ in their immunosuppressive effect. The MLR inhibitory effect of supernatant from I/CB cells was partly blocked by addition of indomethacin. We conclude that MLR inhibiting factors are produced by normal and pathological corneas and by I/CB cells, but the supernatants from these tissues achieve their effect by different means. It is likely that the ability of cornea and I/CB tissues to produce immunosuppressive factors contributes to the success of orthotopic corneal transplants in man.