The polyphenol-rich fraction (WP, 45% polyphenol) prepared from the kernel pellicles of walnuts was assessed for its hepatoprotective effect in mice. A single oral administration of WP (200 mg/kg) significantly suppressed serum glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) elevation in liver injury induced by carbon tetrachloride (CCl 4), while it did not suppress d-galactosamine (GalN)-induced liver injury. In order to identify the active principles in WP, we examined individual constituents for the protective effect on cell damage induced by CCl 4 and d-GalN in primary cultured rat hepatocytes. WP was effective against both CCl 4- and d-GalN-induced hepatocyte damages. Among the constituents, only ellagitannins with a galloylated glucopyranose core, such as tellimagrandins I, II, and rugosin C, suppressed CCl 4-induced hepatocyte damage significantly. Most of the ellagitannins including tellimagrandin I and 2,3- O-hexahydroxydiphenoylglucose exhibited remarkable inhibitory effect against d-GalN-induced damage. Telliamgrandin I especially completely suppressed both CCl 4- and d-GalN-induced cell damage, and thus is likely the principal constituent for the hepatoprotective effect of WP.