The present study was designed to investigate the patterns of allogeneic cytotoxic T cell responses against H-2K and H-2D region products. B10.D2 anti-B10.A(2R) effector cells lysed K-end matched target cells approximately 5 times more efficiently than D-end matched target cells. In contrast, C57BL/10 anti-B10.A effector cells killed K-end or D-end matched target cells equally well, whereas C57BL/10 anti-B10.D2 CTL exhibited a slight preference for D-end matched target cells. These results demonstrate that whole H-2 disparate stimulating populations do not necessarily induce equivalent h-2K and H-2D region-specific CTL responses. The strength of the cytotoxic responses was found to correlate with the number of known serologically detectable specificities shared between the stimulating and target cell populations. The similarities between these allogeneic and MHC-restricted CTL response patterns (which are under Ir-like control) raise the possibility that this regulation reflects the number of K or D region self-antigens that can be recognized in association with a foreign antigenic determinant and suggests that allogeneic responses to major histocompatibility antigens are also self-restricted by MHC gene products. The possibility is considered that such Ir-like control is also a reflection of the amounts of H-2K and H-2D products shed from the cell surface.