Purpose: To determine the extent to which each layer of the mouse cornea displays alloimmuno-genicity or immune privilege. Methods: Intact corneas or individual or combined layers of corneas from normal or cauterized eyes of BALB/c, C57BL/6, and CD95L-deficient B6-gld mice were grafted beneath the kidney capsule of normal BALB/c, B10.D2, BALB.B mice or of BALB/c mice presensitized to donor antigens. Graft fate was assessed clinically and histologically and acquisition of donor-specific delayed hypersensitivity (DH) was assessed at selected intervals after grafting. Results: Full-thickness allogeneic corneas induced vigorous DH and were rejected acutely. Similar results were obtained with allografts of corneal epithelium alone (if supported by syngeneic viable stroma), allografts of epithelium from cauterized corneas (containing Langerhans' cells), and stromal allografts deprived of endothelium. Grafts comprised of stroma plus endothelium (without epithelium) were not rejected, nor did they induce DH unless the graft had no CD95L expression. If stroma-endothelium grafts had no CD95L expression, DH directed against major histocompatibility complex (MHC), but not minor histocompatibility, alloantigens was induced. Moreover, CD95L expressed on stroma-endothelium grafts protected endothelial cells, but not stromal cells, from rejection in presensitized recipients. Conclusions: When grafted to a heterotopic site, the alloimmunogenicity of the normal cornea resides within its epithelial and stromal layers, whereas immune privilege arises from the endothelium. In normal mice, CD95L-expressing endothelium can inhibit the stroma from inducing immunity directed at MHC alloantigens, but in presensitized mice the endothelium can protect itself only from immune rejection.