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Vanillic acid (VA) is one of the most abundant phenolic acids in plants and might be found in high concentrations in vanilla beans and sugar cane molasses. The present study investigated the possible mechanisms underlying the hepatoprotective effect of vanillic acid on thioacetamide (TAA)-induced acute liver failure (ALF). The hepatoprotective effect of vanillic acid was evaluated by the assay of liver function parameters as serum aminotransferases (ALT and AST) as well as total bilirubin level (TB), and oxidative stress markers as hepatic malondialdehyde (MDA), reduced glutathione (GSH) content, and catalase activity (CAT), in addition to inflammatory markers as nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α) and nitric oxide (NO). Furthermore histopathological study of the liver was carried out. Preadministration of vanillic acid significantly lowered the elevated activity of serum AST, ALT enzymes and TB level and restored the hepatic abnormal levels of enzymatic antioxidants and MDA as well as decreased the elevated levels of inflammatory markers induced by TAA administration in a dose-related manner. The chemical pathological changes were consistent with histopathological observations. These results indicate that vanillic acid could be useful in protection against TAA-induced ALF. Its significant hepatoprotective activity could be due to its antioxidative activity in addition to its antiinflammatory properties..