The mixed lymphocyte culture reaction (MLR) ~ through its association with the inheritance of the major histocompatibility antigens has received a great deal of interest in the field of transplantation biology (1). The recent demonstration that specific lymphoid cell types, i.e., 0-antigen-bearing thymusderived lymphocytes (T cells) with allogeneic non-P-antigen-bearing bone marrow-derived lymphocytes ("B" cells), interact to yield a proliferative response, broadens or extends the usefulness of this assay, namely to study the nature of cell-cell interactions (2). Any information, therefore, relating to the genetic control of responses in the MLR may aid in the delineation of the steps involved not only in the biological pathways of cell activation but also in Tand B-cell interaction.The responses, in vitro, to the H-2D antigenic specificities of the mouse provided us with an ideal system in which to study the genetic control of responses in mixtures of allogeneic lymphocytes (3). The data presented in this paper will demonstrate that: (a) genetic material outside of the H-2D region is involved in determining the !evel of the response to H-2D d antigens; (b) the control of the level of responsiveness was found to be a dominant trait; (c) multiple loci are involved in determining the level of MLR responses; (d) one of these loci is associated with the H-2 region though responses to H-2D d specificities were also observed, in the absence of differences between the cell donor strains at the H-2K, H-2I, and H-2S loci; and (e) responses are demonstrable even when genetic information determining MLR responsiveness is also present in the stimulating cell donor; i.e., unlike the H-2-associated specificities, differences