In humans, the HLA-DR molecule is a major stimulatory molecule of allogeneic mixed lymphocyte reactions (MLR) and a major restriction molecule for the presentation of soluble antigens to the T cell. Little is known of the biological function of HLA-DQ. To examine the size of the repertoire of precursor T cells recognizing the autologous or allogeneic HLA-DQ molecule, the frequency of T cells reactive to HLA-DQ was estimated in comparison with T cells reactive to HLA-DR. We made use of a limiting dilution analysis and mouse L cells transfectants expressing the HLA-DR or -DQ molecule, as stimulators. Human T cells recovered from a primary MLR stimulated with allogeneic peripheral blood lymphocytes (PBL) proliferated in response to L cell transfectants expressing HLA class II genes shared by the stimulator cells in the primary MLR. This observation suggested that the HLA class II molecules on L cell transfectants shared to some extent epitopes for alloreactive T cells with those expressed on human PBL. The precursor frequencies of CD4+ T cells reactive to allogeneic or autologous DQ molecules were as high as those of T cells reactive to allogeneic DR molecules and were estimated to be 1/800-1/1800. The frequency of the T cells reactive to autologous DR molecules was low (1/7200-1/16,000). The biological significance of the high frequency of HLA-DQ-reactive precursor T cells is discussed.