THE male-specific transplantation antigen, H-Y, causes rejection of male tissue grafts by genotypically identical female mice(1) and contributes to the rejection of human leukocyte antigen-matched male organ grafts by human females(2). Although first recognized 40 years ago(1), the identity of H-Y has remained elusive. T cells detect several distinct H-Y epitopes(3-5), and these are probably peptides, derived from intracellular proteins, that are presented at the cell surface with major histocompatibility complex (MHC) molecules(6). In the mouse, the gene(s) controlling H-Y expression (Hya) are located on the short arm of the Y chromosome(7,8) between the zinc-finger genes Zfy-1 and Zfy-2 (ref. 9). We have recently identified Smcy, a ubiquitously expressed gene, in this region(10) and its X-chromosome homologue, Smcx(11). Here we report that Smcy encodes an H-YKk epitope that is defined by the octamer peptide TENSGKDI : no similar peptide is found in Smcx. These findings provide a genetic basis for the antigenic difference between males and females that contributes towards a tissue transplant rejection response.