B10.W females were immunized against syngeneic male cells (via the footpad and also i.p. in some strains) and their spleen cells were then restimulated in vitro and tested in the cell-mediated lympholysis assay for H-Y-specific killing of target cells. Only seven of the 33 tested lines were anti-H-Y responders. The effector cells obtained from each of the responder lines were then tested against male and female cells of other B10.W lines, as well as a number of classic B10 congenic lines, and the MHC molecules providing the context for H-Y recognition were identified. They were: Kk, Kw3, Kw7, Kw17, Kw27, Dk, and Dp. None of the strains generated effector cells capable of recognizing the H-Y antigen simultaneously in the context of the K and D molecules. The WOA1 females generated effector cells by using the Kw7 molecule for context of recognition, whereas the WR7 females produced cells recognizing the H-Y antigen exclusively in the context of the Dk molecule despite the fact that both lines share the Kw7 gene. Some of the effector cells cross-reacted with both male and female cells of other strains and this cross-reactivity could be attributed to the recognition of allogeneic MHC molecules controlled by K or D region genes. Interestingly, STA39 females generated Dp- but not Kw3-restricted anti-H-Y responses, whereas SAA48 females generated Kw3- but not Dw3-restricted responses; the Kw3-restricted cells cross-reacted with the Dp molecule. This cross-reaction might explain why the STA39 females do not mount a Kw3-restricted anti-H-Y response. Because the Kw3 + H-Y combination resembles Dp, the anti-Kw3 + H-Y T cells are functionally eliminated when tolerance of Dp molecules is attained in the STA39 mice.