Liver X receptors (LXRs) are nuclear receptors activated by oxidized lipids and were previously implicated in the several metabolic development and inflammatory disorders. Although neutrophils express both LXR-α and LXR-β, the consequences of their activation, particularly during sepsis, remain unknown. Here, we verified that LXR activation reduces neutrophil chemotactic and killing abilities in vitro. Mice treated with LXR agonists showed higher sepsis-induced mortality, which could be associated with reduced neutrophil infiltration at the infectious foci, increased bacteremia, systemic inflammatory response and multi-organ failure. In contrast, septic mice treated with LXR antagonist showed increased number of neutrophils in the peritoneal cavity, reduced bacterial load and multi-organ dysfunction. Importantly, neutrophils from septic patients showed increased ABCA1 mRNA levels (a marker of LXR activation) and impaired chemotactic response toward CXCL8 compared to cells from healthy individuals. Therefore, our findings suggest that LXR activation impairs neutrophil functions, which might contribute to poor sepsis outcome.