Liver X receptors (LXRs) are nuclear receptors previously identified to be important in lipid metabolism. Recent reports suggest that LXR agonists also exhibit anti-inflammatory properties in mouse models of atherosclerosis and contact dermatitis. In the present study, we investigated the effects of LXR agonists on mouse microglia and astrocytes. When chronically activated, these resident-CNS glia have been implicated in the pathology of neuroinflammatory disorders including multiple sclerosis (MS). Our studies demonstrated for the first time that LXR agonists inhibited the production of nitric oxide, the pro-inflammatory cytokines IL-1beta and IL-6 and the chemokine MCP-1 from LPS-stimulated microglia and astrocytes. Furthermore, LXR agonists inhibited LPS-induction of nuclear factor-kappa B (NF-kappaB) DNA-binding activity. These agonists also blocked LPS-induction of IkappaB-alpha protein degradation in microglia, suggesting a mechanism by which these agonists modulate NF-kappaB DNA-binding activity. These studies suggest that LXR agonists suppress the production of pro-inflammatory molecules by CNS glia, at least in part, by modulating NF-kappaB-signaling pathways. Retinoid X receptors (RXRs) physically interact with LXR receptors, and the resulting obligate heterodimer regulates the expression of LXR-responsive genes. Interestingly, a combination of LXR and RXR agonists additively suppressed the production of NO by microglia and astrocytes. Collectively, these studies suggest that LXR agonists may be effective in the treatment of neuroinflammatory diseases including MS.