Two components of a receptor complex for IL-13, the IL-4R and a low affinity IL-13-binding chain, IL-13Rα1, have been cloned in mice and humans. An additional high affinity binding chain for IL-13, IL-13Rα2, has been described in humans. We isolated a cDNA from the thymus that encodes the murine orthologue of the human IL-13Rα2. The predicted protein sequence of murine IL-13Rα2 (mIL-13Rα2) has 59% overall identity to human IL-13Rα2 and is closely related to the murine low affinity IL-13-binding subunit, IL-13Rα1. The genes for both mIL-13-binding chains map to the X chromosome. A specific interaction between mIL-13Rα2. Fc protein and IL-13 was demonstrated by surface plasmon resonance using a BIACORE instrument. Ba/F3 cells that were transfected with mIL-13Rα2 expressed 5000 molecules per cell and bound IL-13 with a single K d of 0.5 to 1.2 nM. However, these cells did not proliferate in response to IL-13, and the IL-4 dose response was unaffected by high concentrations of IL-13. In contrast, the expression of mIL-13Rα1 by Ba/F3 cells resulted in a sensitive proliferative response to IL-13. Consistent with its lower affinity for IL-13, IL-13Rα1. Fc was 100-fold less effective than IL-13Rα2. Fc in neutralizing IL-13 in vitro. These results show that mIL-13Rα2 and mIL-13Rα1 are not functionally equivalent and predict distinct roles for each polypeptide in IL-13R complex formation and in the modulation of IL-13 signal transduction.