<jats:p><jats:bold><jats:italic>Background—</jats:italic></jats:bold>The liver X receptors (LXRs) belong to the nuclear receptor superfamily and act as transcriptional regulators of cholesterol metabolism in several tissues. Recent work also has identified LXRs as potent antiinflammatory molecules in macrophages and other immune cells. Combined changes in lipid and inflammatory profiles are likely mediating the protective role of LXRs in models of chronic injury like atherosclerosis. These beneficial actions, however, have not been illustrated in other models of acute injury such as stroke in which inflammation is an important pathophysiological feature.</jats:p><jats:p><jats:bold><jats:italic>Methods and Results—</jats:italic></jats:bold>We have studied LXR expression and function in the course of experimental stroke caused by permanent middle cerebral artery occlusion in rats and mice. Here, we show that administration of the synthetic LXR agonists GW3965 or TO901317 after the ischemic occlusion improves stroke outcome as shown by decreased infarct volume area and better neurological scores in rats. Neuroprotection observed with LXR agonists correlated with decreased expression of proinflammatory genes in the brain and with reduced nuclear factor-κB transcriptional activity. Loss of function studies using LXRα,β<jats:sup>−/−</jats:sup>mice demonstrated that the effect of LXR agonists is receptor specific. Interestingly, infarcted brain area and inflammatory signaling were significantly extended in LXRα,β<jats:sup>−/−</jats:sup>mice compared with control animals, indicating that endogenous LXR signaling mediates neuroprotection in this setting.</jats:p><jats:p><jats:bold><jats:italic>Conclusion—</jats:italic></jats:bold>This work highlights the transcriptional action of LXR as a protective pathway in brain injury and the potential use of LXR agonists as therapeutic agents in stroke.</jats:p>