Human (T,G)-A-L specific T cell helper factors secreted by in vitro activated peripheral blood lymphocytes of normal donors were characterized. Factors were passed through columns of Sepharose coupled either to antibodies against human immunoglobulin or antibodies against the variable region of the heavy (VH) and light (VL) chains of human immunoglobulin. In addition, the same factors were applied to columns of Sepharose coupled to anti-HLA-DR antibodies or to monoclonal antibodies against human Ia or beta 2-microglobulin. The activity of the antigen specific factors was removed by the anti-VH antibodies and not by anti-VL or anti-human immunoglobulin antibodies. The factors passed through Sepharose coupled to anti-DR antibodies could be removed and eluted from columns of anti-DR antibodies relevant to the donors' DR antigens. The same factors were also removed by a monoclonal antibody (anti-Ia) which recognizes a monomorphic determinant on HLA-DR, but not by monoclonal anti-beta 2-microglobulin. The results suggest that the genetically regulated (T,G)-A-L specific helper factors possess HLA-DR as well as VH determinants in their active moiety.