We have identified the mouse and rat homologs of human interleukin-22 receptor alpha 2 (IL-22Rα2) and compared the localization, structure, and expression of the encoding murine and human genes. The mouse IL-22Rα2-encoding gene is located on chromosome 10A3 between, like in human, the genes for interferon-gamma R1 and IL-20R1. It spans a region of approximately 10 kb therefore being three times shorter than the human gene. Although the overall gene structure in both species is similar, the mouse gene lacks a counterpart to the third coding exon of the human gene known to be alternatively spliced. Like in human, mouse and rat IL-22Rα2 exist only as soluble receptors as deduced from the lack of transmembrane and intracellular domains encoding sequences. Quantitative expression analyses showed, analogically to the human system, a limited tissue distribution of mouse IL-22Rα2 mRNA. Differential modulation of IL-22Rα2 mRNA expression was observed upon systemic inflammation in mice in spleen, thymus, and lymph node.