Among various tumors induced by human papilloma virus (HPV), flat warts are unique in that they show a systemic regression phenomenon after sudden occurrence of inflammation in all the tumors, leaving permanent immunity to flat warts in the host. When studied immunohistochemically, the presence of HPV antigen using papilloma virus genus‐specific antiserum in 31 cases of regressing flat warts was not found; whereas it was demonstrated in the nuclei of upper epidermal cells of ordinary flat warts in 12 of 19 cases (63%). T‐cell phenotype assessment in nine regressing flat warts using monoclonal antibodies showed that helper/inducer subsets constituted a major peritumoral dermal infiltrate with a moderate number of intermingling OKT6+ cells. In contrast, the tumoral epidermis was invaded by almost equal number of suppressor/cytotoxic T‐cells and helper/inducer T‐cells, where at least some keratinocytes also expressed HLA‐DR antigen in addition to Langerhans cells. Most T‐cells expressed HLA‐DR antigen, a marker of activation, but only a small number of them were Tac antigen+, i.e., bearing interleukin 2 receptors. Leu 7+ natural killer cells were seldom found in the infiltrate. These data provide evidence that T‐cell‐mediated immune attack against tumor cells and not against intranuclear HPV antigen, induces the systemic spontaneous regression of numerous flat warts in humans.