T cell mediated immune responses against the cornea specific protein BCP 54 have been observed in patients with uveitis, Fuchs' heterochromic cyclitis, and corneal disease. The pathophysiological role of this anti-BCP 54 response in corneal disease is not known. In order to ascertain whether the presence of such an immune response is related to the corneal disease itself or related to genetic influences, the anti-BCP 54 response was determined in 104 patients with severe corneal disease, using a monocyte migration inhibition assay. The results were compared with the presence of a variety of ocular parameters as well as with the distribution of HLA antigens in these patients. While only 7% of healthy controls responded to BCP 54, 37% of the patients showed a positive response (p = 0.002); in particular, patients with previous graft rejection, non-herpetic keratitis, and bullous keratopathy reacted against BCP 54. No relation with known risk factors for corneal transplantation, such as corneal neovascularisation, was observed. No significant association with the presence of any of the HLA antigens was observed. It was concluded that the main inducer of an anti-BCP 54 response is corneal disease itself, and that the presence of corneal disease is able to break the immunological privilege typical of normal corneas.