Although interleukin-13 receptors (IL-13R) are overexpressed on several head and neck cancer cell lines, a majority of cell lines express only low levels of IL-13R. We have found that the primary interleukin-13-binding protein IL-13Ralpha2 chain plays an important role in ligand binding and internalization. We showed that the gene transfer of IL-13Ralpha2 chain into various solid tumor cell lines that express few IL-13Rs can dramatically sensitize cells to the cytotoxic effect of a recombinant chimeric protein composed of interleukin-13 and a mutated form of Pseudomonas exotoxin A, IL13-PE38QQR. Based on the expression of IL-13R, we have classified five head and neck cancer cell lines into two groups: (a) IL-13Ralpha2 chain-positive cell lines (SCC-25 and KCCT873); and (b) IL-13Ralpha2 chain-negative cell lines (A253, YCUT891, and KCCT871). By plasmid-mediated stable gene transfer, we demonstrate that not only IL-13Ralpha2 chain-positive head and neck cancer cell lines but also IL-13Ralpha2 chain-negative cell lines can dramatically increase sensitivity to IL-13 toxin by 520-1000-fold compared with mock-transfected control cells after genetic alteration to express high levels of the IL-13Ralpha2 chain. In animal studies, i.p. or intratumoral administration of IL13-PE38QQR given daily or on alternate days for 3-5 days showed dramatic tumor response with complete remission in intratumorally injected tumors in both IL-13Ralpha2 chain-positive and -negative but transfected with IL-13Ralpha2 chain head and neck tumor implanted s.c. in nude mice. These results demonstrate that by using a combination approach of gene transfer and systemic or locoregional cytotoxin therapy, the IL-13R represents a new potent target for head and neck cancer therapy.