Background and purpose: Subset of macrophages within the atheroma plaque displays a high glucose uptake activity. Nevertheless, the molecular mechanisms as well as the pathophysiological significance of this high glucose need remain unclear. While a role for hypoxia and hypoxia inducible factor 1α has been demonstrated, the contribution of lipid microenvironment and more specifically oxysterols is yet to be explored. Experimental approach: Human macrophages were conditioned in the presence of homogenates from human carotid plaques and expression of genes involved in glucose metabolism was quantified. Correlative analyses between gene expression and the oxysterol composition of plaques were performed. Key results: Conditioning of human macrophages by plaque homogenates induces expression of several genes involved in glucose uptake and glycolysis including glucose transporter 1 (GLUT1), and hexokinases 2 and 3 (HK2 and HK3), This activation is significantly correlated to the oxysterol content of the plaque samples and is associated with a significant increase in the glycolytic activity of the cells. Pharmacological inverse agonist of the oxysterol receptor Liver X Receptor (LXR) partially reverses the induction of glycolysis genes without affecting macrophage glycolytic activity. Chromatin immunoprecipitation analysis confirms the implication of LXR in the regulation of GLUT1 and HK2 CONCLUSIONS AND IMPLICATIONS: While our work supports a role of oxysterols and LXR in the modulation of macrophage metabolism in atheroma plaques, it also highlights some LXR-independent effects of plaques samples. Finally, this study identifies the hexokinase HK3 as a promising target in the context of atherosclerosis.