CCAAT/enhancer binding protein (C/EBP) transcription factors play essential roles in regulating an array of cellular processes, including differentiation, energy metabolism, and inflammation. In this report we demonstrate that both C/EBPalpha and C/EBPbeta activate the promoter driving transcription of the tumor necrosis factor receptor 1 (TNFR1). TNFR1 is the major receptor for tumor necrosis factor (TNF), a critical cytokine mediator of the inflammatory response. Although the TNFR1 protein has been shown to be regulated through post-translational modifications, very little is known about the transcriptional regulation of the TNFR1 gene. Here we have identified a specific C/EBP binding site within the TNFR1 promoter, and shown that this site is required for both C/EBPalpha and C/EBPbeta activation of the promoter in reporter gene assays. Furthermore, we show that both C/EBPalpha and C/EBPbeta are bound to the TNFR1 promoter in cells using chromatin immunoprecipitation assays. Finally, we demonstrate that reducing the level of C/EBPalpha and C/EBPbeta expression in cells using siRNA technology leads to decreased expression of the TNFR1 protein. These results suggest that the C/EBPalpha and C/EBPbeta transcription factors enhance expression of the TNFR1 protein in cells. Given that TNF and C/EBPbeta are known to activate each other's expression, C/EBPbeta may greatly amplify the initial TNF signal through a positive auto-regulatory mechanism.