Interleukin (IL)-4 and IL-13 share the type II IL-4 receptor for cell signaling. We show that despite expressing the necessary signaling components, glioblastoma cells failed to respond to either IL-4 or IL-13. This was in part because of the expression of a high-affinity IL-13-binding transmembrane protein IL-13Rα2 that inhibited IL-13-mediated Stat6 activation by acting as a decoy receptor. In contrast, normal human astrocytes that did not express the IL-13Rα2 gene efficiently induced Stat6 activation in response to both IL-4 and IL-13. Transient expression of the IL-13Rα2 transgene in nonexpressing heterologous cells inhibited not only IL-13- but also IL-4-mediated signal transduction and Stat6-responsive gene expression. The inhibition was likely mediated through the physical interaction between the short intracellular domain of the IL-13Rα2 protein and the cytoplasmic domain of the IL-4Rα chain that harbors the Stat6 docking sites. Thus, IL-13Rα2 acts as an inhibitor of IL-4-dependent signal transduction pathways via a novel mechanism that is independent of ligand binding.