The H60 minor histocompatibility (H) antigen peptide is derived from a glycoprotein that serves as a ligand for the stimulatory NKG2D receptor. We show that this peptide is remarkably immunodominant in that it competes effectively with MHC alloantigens, is efficiently crosspresented by host antigen-presenting cells (APCs), and readily elicits naive CD8 T cell responses in vitro. H60 immunodominance is neither a consequence of NKG2D engagement nor competition among minor H antigens on APCs. Instead, H60 immunodominance is a consequence of an abnormally high naive precursor frequency of H60 peptide reactive CD8 T cells. Understanding why the H60 peptide is so immunogenic has important implications in tissue transplantation and vaccine design.