The expression of transforming growth factor-β2 (TGF-β2) appears to play a strong role in the establishment and progression of glial tumors. In particular, elevated expression of TGF-β2 appears to be responsible for the impaired cell-mediated immunity often observed in patients with a glioblastoma. This study examined the regulation of the TGF-β2 at the transcriptional level in the U87MG glioblastoma cell line. We demonstrate that a cAMP response element/activating transcription factor (CRE/ATF) site and an E-box motif located just upstream of the transcription start site are essential for the transcription of the TGF-β2 gene in U87MG cells. Gel mobility analysis determined that activating transcription factor-1, and possibly cAMP-responsive element binding protein, binds to the CRE/ATF site, and upsteam stimulatory factor (USF) 1 and USF2 bind to the E-box motif. Interestingly, expression of a dominant negative USF protein down-regulates TGF-β2 activity by 80–95% in glioblastoma cells. We conclude that the binding of transcription factors, in particular the USF proteins, to the TGF-β2 promoter is essential for its expression and possibly its up-regulation in glioblastomas.