Several features of HLA-G's sequence and expression pattern distinguish HLA-G from its classical counterparts. These features, including HLA-G's limited polymorphism and its expression at the maternal-fetal interface, have been used as a basis for suggesting a distinct functional role for this nonclassical class I HLA molecule. On the other hand, published data do demonstrate that HLA-G has much in common with its classical counterparts. It associates with β2-microglobulin and cytosolic peptides, it binds to CD8, and its presence can inhibit NK-cell-mediated lysis of HLA-G-bearing target cells. To develop a model in which HLA-G's function could be more thoroughly studied, we produced several HLA-G-expressing transgenic mouse strains. We report here the results of skin graft experiments which show that nontransgenic mice reject HLA-G-expressing transgenic murine skin as foreign and that this rejection is associated with the presence in the recipient of lymphocytes capable of specifically lysing HLA-G-expressing cells. In addition, experiments are described which demonstrate that HLA-G transgenic mice recognize HLA-G as a 'self' molecule. Together the reported data demonstrate that HLA-G is capable of stimulating an HLA-G-restricted CTL response, that HLA-G molecules can serve as target molecules in lyric interactions with CTLs, and that HLA-G is involved in education of the lymphocytic repertoire of HLA-G transgenic mice.