Despite advances in diagnosis and treatment, survival rates for patients with head and neck cancer have remained unchanged for the last 30 years. In an attempt to develop novel therapeutic agents, we have observed that a variety of murine and human carcinoma cells expresses high levels of receptors for interleukin 4 (IL-4) in vitro and in vivo. Here, we demonstrate that 17 head and neck cancer cell lines also express surface IL-4 receptors (IL-4R) and IL-4 binds to IL-4R on one cell line studied with low affinity ((k)d = 37.9 +/- 0.4 nM). The investigation of the subunit structure of IL-4R demonstrated that head and neck cancer cell lines expressed mRNA for IL-4R beta chain (also known as IL-4R alpha) and IL-13R alpha' chain (also known as IL-13R alpha1). However, no cell line expressed IL-2R common gamma-chain, which is known to be shared with IL-4R in immune cells. IL-4R is functional because IL-4 strongly induced activation of signal transducers and activators of transcription 6 (STAT-6) in these cell lines. A fusion protein, IL4(38-37)-PE38KDEL, containing translocation and enzymatic domains of Pseudomonas exotoxin and a circularly permuted human IL-4 was found to be highly and specifically cytotoxic to IL-4R-positive head and neck cancer cells, as determined by protein synthesis inhibition assay and confirmed by clonogenic assay. IL4(38-37)-PE38KDEL induced DNA fragmentation and condensation of nuclei indicative of apoptotic cell death. These results establish uniform expression of IL-4R on head and neck cancer cell lines and IL-4 toxin IL4(38-37)-PE38KDEL as a novel therapeutic agent for the possible treatment of human head and neck cancers.