Interleukin (IL)-21 induces proliferation of activated T and natural killer (NK) cells and enhances the lytic function of NK cells. IL-23, a heterodimer composed of p19 and p40 molecule, can also, enhance T cell proliferation and interferon-gamma production from activated T cells; however, its effects on NK cells are currently unknown. We therefore examined whether human tumors expressing IL-21 or IL-23 could produce antitumor effects in inoculated nude mice. Esophageal tumor T. Tn cells were retrovirally transduced with the IL-21 gene (T.Tn/IL-21) or the p19-linked p40 genes (T. Tn/IL-23). The proliferation in vitro and the class I expression of the major histocompatibility complexes of these transduced cells were not different from those of parent cells. T.Tn/IL-21 and T.Tn/IL-23 cells developed small tumors in nude mice, but the tumors regressed spontaneously thereafter in contrast to parent tumors. Expressed IL-21 or IL-23 in human esophageal tumors can produce antitumor effects in a T cell-defective condition.