It has been reported that over-expression of GRP75 can protect cells under different types of stress. In this study, we investigated the protective effect of GRP75 on the liver both in vivo and in vitro. To evaluate the effect of GRP75 over-expression on oxidative damage in the liver in vitro, cell viability and the mitochondrial function of GRP75-overexpressing HL-7702 cells and control transfected cells were monitored during H(2)O(2) treatment. In vivo, liver fibrosis was induced in rats by carbon tetrachloride (CCl(4)) injection for 8 weeks. The GRP75-overexpressing vector was randomly injected into rats before fibrosis was established to study the inhibitory effect of GRP75 on hepatic fibrosis. Liver injury and mitochondrial function were assessed. On H(2)O(2) treatment, GRP75-overexpressing HL-7702 cells exhibited more moderate cell damage than control HL-7702 cells. Both groups of cells showed a decrease in ATP following an early increase on H(2)O(2) treatment, and the mitochondrial membrane potential also decreased similarly in these two groups of cells. Control HL-7702 cells showed an immediate and rapid increase in reactive oxygen species accumulation after the onset of H(2)O(2) treatment, and this accumulation was slowed and reduced in GRP75-overexpressing cells. Western blotting revealed that cytochrome c was greater in control HL-7702 cells than in GRP75-overexpressing HL-7702 cells. Compared with the CCl(4)-only rats, serum alanine transaminase and aspartate aminotransferase were significantly lower in CCl(4)-treated rats transfected with the GRP75 vector (P < 0.01). ATP concentrations decreased in both groups of rats treated with CCl(4), but were higher in the GRP75-overexpressing CCl(4)-treated group than in CCl(4)-only rats. Cytochrome c expression was lower in GRP75-overexpressing rats than in CCl(4)-only rats.