Induction of antigen-specific tolerance to transplantation antigens is desirable to control host-versus-graft and graft-versus-host reactions.Intranasal administration of individual major histocompatibility complex (MHC) class II-restricted HY peptides induces indefinite survival of syngeneic male skin grafts and allows engraftment of male bone marrow.Humans make male-specific T-cell responses to HY peptides from the same genes, SMCY, UTY, and DBY, strongly conserved across mammalian species, and from additional ubiquitously transcribed human Y chromosome genes, RPS4Y and DFFRY.