MHC class I-related chain A (MICA) is an HLA-related, polymorphic gene the product of which may be recognized by a subpopulation of intestinal gamma delta T cells and may play a role in the activation of a subpopulation of natural killer cells. Using anti-MICA specific rabbit sera we previously demonstrated that freshly isolated monocytes, keratinocytes, fibroblasts, and endothelial cells express MICA. To analyze whether MICA may be a target for specific antibodies in sera of transplanted patients, we produced three recombinant MICA proteins consisting of the alpha 1, alpha 2, and alpha 3 domains, and used them in an enzyme-linked immunosorbent assay. We found that several patients had specific antibodies against MICA. Most of them were detected in serum samples collected at different times after organ rejection. Although this finding raises the question of how these patients became immunized, the fact that the polymorphic, HLA-like MICA molecule, expressed at the cell surface of endothelial cells, is recognized by specific antibodies in sera of transplanted patients, suggests the MICA may be a target molecule in allograft rejection.