The present study was aimed to investigate the preventive effects of rebamipide on the multiple organ dysfunction in a rat model of circulatory shock induced by bacterial endotoxin (E. coli lipopolysaccharide; LPS) in comparison with that of methotrexate. Endotoxemia for 6 hours resulted in little change in the levels of hemoglobin and neutrophils. However, treatment with methotrexate decreased significantly the numbers of circulating neutrophils. Significant increases in serum alanine aminotransferase (ALT,958 $pm$ 250 lU/L, p<0.001) and aspartate aminotransferase (AST, 1350 $pm$ 295 lU/L, p<0.001) levels induced by endotoxemia were significantly decreased by rebamipide and methotrexate. The increased level of lactic acid dehydrogenase (LDH) by LPS (2850 $pm$ 467 lU/L, p<0.05) was significantly inhibited by rebamipide, but not by methot.elate. The elevated serum creatinine (1.2$pm$0.1, p.0.05) and urea levels (55.3$pm$6.5 mg/dL, p.0.01) by LPS were also decreased by rebamipide, but not by methotrexate. In line with these results, the plasma concentration of tumor necrosis factor-$alpha$ (TNF-7,167 $pm$ 20 pg/mL) was significantly increased upon injection of endotoxin at 1 hour by 1570$pm$100 pg/mL, and declined to 312$pm$35 pg/mL at 6 hours. The TNF-$alpha$ level at 6 hours was significantly decreased by rebamipide to 207$pm$8 pg/mL (P<0.05). Taken together, it is summarized that rebamipide inhibits the development of multiple ogran dysfunction by inhibition of neutrophil activation in association with inhibition of TNF-$alpha$ formation in a murine model of endotoxemia.