Background: IL-13Ra2 is overexpressed by gliomas but not by normal tissue. However, the molecular basis for IL-13Ra2 overexpression in gliomas is unknown.Methods: In the present study we have investigated the regulatory mechanisms that are responsible for the expression of IL-13Ra2 with mutation analysis, quantitative RT-PCR, Flow cytometry analysis, transcription factor binding assay and Elisa.Results: Our results reveal a complex mechanism for regulating IL-13Ra2 expression that involves at least 2 promoters and 4 transcripts of human IL-13Ra2. Transcription factors NFAT and AP1 are necessary and essential for the expression of this GBM related transcript, and are responsible for the high level of expression of IL-13Ra2 in GBM. Most interestingly, we found that expression of this transcript results in the production of a secreted form of IL-13Ra2 and thus may have the potential to be used as a diagnostic biomarker for GBM patients and other cancer patients that express the soluble form of this receptor.Conclusions: This study is the first to characterize the role of NFAT and AP1 in the regulation of IL-13Ra2 expression, and provides insight into understanding the high levels of IL-13Ra2 expressed by GBM cells.