The farnesoid X receptor (FXR) is a ligand-activated transcription factor that regulates genes involved in bile acid metabolism. Accumulating data demonstrate that FXR has an anti-inflammatory activity. The present study aimed to investigate the effect of obeticholic acid (OCA), a novel synthetic FXR agonist, on D-galactosamine (GalN)/lipopolysaccharide (LPS)-evoked acute liver injury. All mice except controls were intraperitoneally injected with GalN (300 mg/kg) plus LPS (2.5 μg/kg). Some mice were pretreated with OCA (10 mg/kg) 48, 24 and 1 h before GalN/LPS. As expected, pretreatment with OCA alleviated hepatocyte apoptosis at early and middle stages of GalN/LPS-induced acute liver failure. By contrast, pretreatment with OCA augmented hepatic injury and inflammatory cell infiltration at middle stage of GalN/LPS-induced acute liver failure. Additional experiment found that OCA inhibited hepatic NF-κB activation at early and middle stages of GalN/LPS-induced acute liver failure. Interestingly, OCA inhibited hepatic proinflammatory cytokine tnf-α and il-6 but upregulated hepatic anti-inflammatory cytokine il-10 at early stage of GalN/LPS-induced acute liver failure. By contrast, OCA suppressed hepatic anti-inflammatory cytokine tgf-β and il-10 at middle stage of GalN/LPS-induced acute liver injury. These results suggest that FXR agonist OCA differentially regulates hepatic injury and inflammation at different stages of GalN/LPS-evoked acute liver failure.