The study of mouse congenic strains, which differ at loci determining differentiation antigens, has led to the discovery of six previously unreported histocompatibility loci— H(Ly-1), H(Ly-2-N8), H(Ly-2-N16), H(Ly-2, Ly-3), H(Ea-2), and H(Tla). Each of these loci determines skin graft rejection and most have been shown to determine tumor graft rejection as well. Two of these loci, H(Ly-2-N16) and H(Ea-2), were detectable only after preimmunization procedures were employed. A synergistic interaction was found between two of the loci, where preimmunization with both an H(Ly-2-N8)- and H(Ly-2-N16)-incompatible graft was necessary in order for animals to respond to an H(Ly-2-N16) difference alone. H(Ly-1) and H(Tla) caused unusual rejection patterns. First skin grafts were often rejected where later ones were accepted. The H(Tla) locus should be very close to the H-2 complex of the mouse and is an example of a histocompatibility gene whose presence is not revealed by hemagglutination or cytotoxicity tests.