Liver X Receptors (LXR) control cholesterol metabolism and exert anti-inflammatory actions in activated macrophages. However, their contribution to human macrophage polarization in the absence of pathogenic stimuli remains unclear. In fact, the LXR pathway has been reported to be significantly enriched in pro-inflammatory synovial macrophages from rheumatoid arthritis patients as well as in immunosuppressive tumors-associated macrophages from human metastatic colon tumors. To determine the role of LXR on macrophage differentiation and polarization, we have analyzed the contribution of LXR to the acquisition of the inflammatory and T-cell-activating functions of human monocyte-derived macrophages. We now report that LXR activation prompts the acquisition of a pro-inflammatory gene signature in human macrophages, whereas LXR inactivation results in enrichment of an anti-inflammatory gene profile. Accordingly, activation and inhibition of LXR oppositely alter the production of cytokines (e.g., TNF, IL1b, CCL17, CCL19, IFNb1) and T cell stimulation activities associated to human macrophage polarization. Mechanistically, the LXR-stimulated macrophage polarization shift relies on their ability to modulate the expression of MAFB and MAF, which govern the acquisition of the macrophage anti-inflammatory profile. The pathological significance of the LXR-mediated macrophage polarization shift was demonstrated by the ability of LXR agonists to modulate macrophage polarization promoted by either tumor-derived ascitic fluids or by synovial fluid from rheumatoid arthritis patients. As a whole, our results demonstrate that LXR activation prompts the acquisition of a pro-inflammatory transcriptional and functional specialization in human macrophages .