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Here, we investigate the role of the transcriptional co-repressors C-terminal binding protein (CTBP) 1 and 2 in murine and human macrophage activation using loss-of-function models to show that CTBP2 but not CTBP1 controls inflammatory gene expression. We find that CTBP2 occupies cis-regulatory elements of inflammatory genes together with the transcription factors NF-κB and AP-1 and forms a co-repressor complex. Rescue of Ctbp1/2 double knockout cells with WT, oligomeric CTBP2 attenuates inflammatory responses, whereas a monomeric mutant does not. Differential profiling of CTBP2's WT and monomeric interactome confirms oligomer-specific interactions with multiple repressors. Conversely, monomers retain the ability to interact with AP-1 and RNA polymerase II, boosting gene expression. Our findings point to an important function for CTBP2 in fine-tuning inflammatory gene expression, potentially unveiling novel therapeutic targets for the treatment of inflammatory diseases.