Although rare, acute liver failure (ALF) is associated with high levels of mortality, warranting the development of novel therapies. Nuclear factor-kappa B (NF-kappa B), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) play roles in ALF. Lipoxin A4 (LXA4) has been shown to alleviate inflammation in non-hepatic tissues. In the present study, we explored whether LXA4 exerted hepatoprotective effects in a rat model of ALF. A rat model of ALF was generated by intraperitoneal injections of D-galactosamine (300 mg/kg) and lipopolysaccharide (50 mu g/kg). Animals were randomly assigned to: control group (no ALF); model group (ALF); and the groups treated with a low dose (0.5 mu g/kg), medium dose (1 mu g/kg), and high dose (2 mu g/kg) of LXA4 (all with ALF); and pyrrolidine dithiocarbamate (PDTC)-treated group (ALF and 100 mg/kg PDTC, an inhibitor of NF-kappa B). Liver histology was measured using H&E staining, serum levels by ELISA, and liver mRNA expression was measured by RT-PCR for the detection of the pro-inflammatory cytokines TNF-alpha and IL-6. Liver cell apoptosis (as measured using the TUNEL method and examining caspase-3 activity), and Kupffer cell NF-kappa B activity [using an electrophoretic mobility shift assay (EMSA)] were examined. Serum levels of transaminases, TNF-alpha and interleukin-6 (IL-6) were substantially higher in the model group compared to controls. In the model group, significant increases in TNF-alpha and IL-6 mRNA expression, TUNEL-positive cells, and caspase-3 activity in the liver tissue were noted. LXA4 improved liver pathology and significantly decreased the indicators of inflammatory response and apoptosis in a dose-dependent manner. High-dose LXA4 provided better protection than PDTC. LXA4 administration significantly decreased NF-kappa B expression in hepatocytes and Kupffer cells. These results indicated that LXA4 inhibited NF-kappa B activation, reduced the secretion of pro-inflammatory cytokines, and inhibited apoptosis of liver cells, thereby exerting protective effects against ALF.