The discovery of functional crosstalk between WNT and NF-κB signaling has established a more complex role of these two pathways in inflammation and cancer. However, the molecular mechanisms of the crosstalk and its biological consequences are largely unknown. Here, we show that WNT/β-catenin signaling selectively inhibits the expression of a proinflammatory subset of IL-1β-induced NF-κB target genes. WNT/β-catenin signaling does not affect nuclear translocation of RelA or its association with CBP, but reduces CBP-mediated acetylation and chromatin recruitment of RelA. Thus, β-catenin selectively regulates NF-κB gene expression through its negative effects on RelA acetylation. This anti-inflammatory effect may be relevant for cancer treatment.