Lethally irradiated C.B-17 +/+, C.B-17 scid/scid (severe combined immunodeficiency, SCID), BALB/c-nu/nu (nude), and C57BL/6 (B6) mice were challenged with H-2-homozygous or H-2-heterozygous totally allogeneic bone marrow cell (BMC) grafts. Some of the irradiated mice were immunized simultaneously with large numbers of irradiated marrow and spleen cells syngeneic with the viable BMC transferred. Irradiated SCID and nude mice, devoid of T cells but with normal NK cell function, were able to reject H-2-homozygous BMC grafts within 4 d. However, they were unable to reject H-2-heterozygous BMC allografts by 7 d even if they were immunized. B6 and C.B-17 +/+ mice were able to reject H-2 heterozygous BMC allografts by 7-8 d, but not as early as 4 d, if they were immunized. The rejection of H-2-homozygous BMC on day 4 was inhibited by administration of anti-NK-1.1 antibodies, but not by anti-Lyt-2 antibodies. Conversely, the rejection of H-2-heterozygous allogeneic BMC on day 8 was prevented by anti-Lyt-2 but not by anti-NK-1.1 antibodies. The data indicate that both NK cells and Lyt-2+ T cells can mediate rejection of allogeneic BMC acutely, even after exposure of mice to lethal doses of ionizing irradiation. NK cells appear to recognize Hemopoietic histocompatibility (Hh) antigens on H-2 homozygous stem cells. The inability of SCID and nude mice to reject H-2 heterozygous totally allogeneic BMC indicate that NK cells do not survey donor marrow cells for self H-2 antigens and reject those cells that express nonself H-2 antigens. The T cells presumably recognize conventional H-2 antigens (probably class I) under these conditions.