B-cell activating factor (BAFF) is critical for maintaining the development and homeostasis of B cells. Overexpression of BAFF is associated with autoimmune diseases and malignant B lymphoma. BAFF receptor (BAFF-R) was found to be a specific receptor of BAFF. It not only plays a significant role in splenic B-cell maturation but also works as a major mediator in BAFF-dependent costimulatory response in peripheral B and T cells. Previous studies have demonstrated that BAFF-R is related to several diseases; however, the molecular mechanism of BAFF-R genic transcription has not been clearly defined. The aim of this study was to investigate the transcriptional regulation of the BAFF-R gene. This study was designed to clone and characterize the 5'-regulatory region of the human BAFF-R gene and determine the mechanisms involved in its transcriptional regulation. In addition, the effects of interferon (IFN)-gamma and BAY11-7082 (inhibitor of nuclear factor [NF]-kappaB) on the expression and promoter activity of BAFF-R were examined. The results showed that the sequence between -1420 and +261 could be a core promoter region, and -1562 and -1420 bp harbored a transcriptive silencer. IFN-gamma promoted BAFF-R promoter activity and upregulated BAFF-R mRNA expression. BAY11-7082 (inhibitor of NF-kappaB) exhibited an inhibitory effect on BAFF-R promoter activity and downregulated BAFF-R mRNA expression. Our data provided novel evidence to clarify the mechanism of transcriptional regulation of BAFF-R and illustrated that IFN-gamma and NF-kappaB pathway were involved in regulating BAFF-R expression. Thus some BAFF-R-related diseases might be cured by blocking transcriptional regulation of BAFF-R and reducing its expression.