This study was undertaken to investigate the nature of the immunogenic moiety recognized by the human T cell which proliferates in response to tetanus toxoid (TT) antigen. Immunosorbent-purified anti-TT IgG antibodies failed, even when added in great excess, to inhibit T cell proliferation in response to TT. Urea-denatured (UD) TT antigen containing less than 1% native TT, as assessed by its reactivity with antibodies raised against native TT, triggered proliferation in T cells to an extent equal to that seen with native TT. The proliferative response to UDTT was seen only in T cells obtained from donors immune to TT and was inhibited by antisera to DRw antigens of the cell donor. T cells responding to TT and to UDTT essentially overlapped because exposure to 5'-bromo-2-deoxyuridine and light of T cells prestimulated with TT or UDTT abolished the specific response to both forms of the TT antigen but not to phytohemagglutinin or to Monilia antigen. It is concluded that proliferating human T cells recognize determinants which differ from those that elicit an antibody response and which may arise as a result of antigen processing by macrophages. The implications of these present results on the nature of the human T cell receptor for antigen are discussed.