Cytotoxic T-cell responses against the H-Y antigen in mice are under the control of major histocompatibility complex genes. Not only must cytotoxic T cells recognize both H-Y antigens and "self" H-2K/D molecules to lyse male target cells, but also "appropriate association" between H-Y antigens and H-2K/D antigens is required to induce such cytotoxic responses. Furthermore, it is suggested that appropriate association with H-2-I antigens may also be required to generate H-Y specific helper cells for the cytotoxic response. BALB/c(KdIdDd) mice are nonresponders against syngeneic H-Y antigens, because they lack appropriate associative H-2K/D antigens. This results in the failure of generation of anti H-Y cytotoxic cells, although helper cells may be induced. F1 hybrid mice (BALB/c X C3H/He)F1 or H-2 recombinant mice C3H-OH(KdIdDk) are responders, because H-2Dk (and H-2Kk in the F1) molecules offer appropriate association to H-Y antigens. We here report that allophenic chimeras (H-2d reversible H-2k) and irradiation bone marrow chimeras [H-2d + H-2k leads to F1(H-2d X H-2k)] generate anti-H-Y cytotoxic responses but that cells of the BALB/c(H-2d) genotype comprise most if not all of the cytotoxic cells. A working model is proposed to account for major histocompatibility complex control over anti-H-Y cytotoxic T-cell responses.