C-Reactive protein (CRP) is a major acute-phase response protein, which is activated by various cytokines. We investigated the mechanism of TNF-α-induced CRP expression and found that the p50 subunit of NF-κB was responsible for the transcriptional activation of CRP. Since the p50 protein acts as a positive regulator of CRP expression without an inherent transactivation domain, we looked for an interaction partner that could provide p50 with such a domain. We found that β-catenin enhanced the expression of a CRP mRNA in concert with p50 subunit. Protein–protein interaction between p50 and β-catenin was important for CRP expression and their interactions to CRP promoter were induced after TNF-a treatment. Since gene expression depends upon the proximity of promoters and distal regulatory sites, we explored the long-range genomic interaction at the CRP locus by chromosome conformation capture (3C). We identified a binding site for β-catenin in the downstream of CRP gene by 3C and confirmed TNF-α-induced association of β-catenin and p50 by chromatin immunoprecipitation and co-immunoprecipitation assays. Our findings provide evidence that transcription of the CRP gene depends upon p50 and β-catenin proteins, which is accompanied by close proximity between promoter and the downstream region of CRP gene.