BACKGROUND: High-fat enteral nutrition reduces the inflammatory response following hemorrhagic shock in the rat. AIMS: We hypothesized that this intervention might also ameliorate the remote organ injury to the liver associated with this model. METHODS: Male Sprague-Dawley rats were either starved or fed low-fat or high-fat isocaloric isonitrogenous feed prior to nonlethal hemorrhagic shock induced by a 40% reduction in the blood volume. Animals were sacrificed at 90 minutes or 24 hours after injury. Liver cell damage was assessed by histology and long polymerase chain reaction (PCR) to detect mitochondrial DNA damage. Stress protein expression was measured by Western blot and mRNA expression by real-time PCR and immunohistochemistry. RESULTS: Animals fed a low-fat diet had the same severity of liver injury as starved animals and increased expression of stress proteins. Animals fed a high-fat diet had minimal liver injury, no evidence of mitochondrial DNA damage, and significantly lower expression of stress proteins. This effect is associated with preservation of hepatocellular morphology, attenuation of mitochondrial DNA damage, and a reduced stress protein response to injury. CONCLUSIONS: High-fat enteral nutrition protects the liver from the remote effects of hemorrhagic shock, but the mechanism of this effect is not yet known.