Fourteen noncytotoxic human helper T cell clones were examined for autocrine proliferative responses and cytotoxicity to tumor cells after stimulation with 12-O-tetradecanoylphorbol 13-acetate (TPA) and ionomycin (Io). Although all clones responded to alloantigen, they could be divided into two groups based on their proliferative response or lack of it to TPA/Io. Nonresponders could not be converted to responder status by addition of interleukin (IL) 1 or indomethacin to the cultures. Responder status did not correlate with any of the following properties of the clones: originating donor, recognitive specificity, B cell helper activity, proliferative response to IL 2 or 4, lymphokine secretory capacity or density of expression of antigen receptors, CD4 or HLA class II molecules. Responder status did, however, correlate with the ability of TPA/Io to induce major histocompatibility complex-unrestricted cytolytic activity directed towards natural killer-resistant tumor cells. These results divide human helper cells into two types on the basis of induction of anti-tumor cytotoxicity.