It is known that o-, m- and p-cresols exert a toxic effect on rat liver cells. However, there is little information on the mechanism for the hepatotoxicity of cresols. We, therefore, investigated the effects of o-, m-, and p-cresols on the bioenergetic system using isolated rat liver mitochondria. When o-, m- or p-cresol was added to liver mitochondria with glutamate or succinate at concentrations of 0.3 to 6.0 mumol/mg protein, each cresol isomer reduced the rate of state 3 respiration dose-dependently. Three cresol isomers at 6.0 mumol/mg protein each inhibited state 3 respiration in liver mitochondria with glutamate or succinate by about 60 or 20%, respectively. The three isomers affected NAD- and succinate-linked respirations in liver mitochondria, by which the respiratory control ratio was dose-dependently attenuated. The inhibitory effects of o-, m- and p-cresols on the NAD-linked respiration were stronger than those on the succinate-linked respiration. However, three cresol isomers had little effect on the P/O ratio in liver mitochondria with glutamate or succinate. Three cresol isomers at 15 mumol/mg protein each induced the swelling in the absence of Ca2+ in medium and accelerated the swelling of liver mitochondria in the presence of Ca2+ in medium. These results indicate that o-, m- and p-cresols inhibit liver mitochondrial respiration and induce or accelerate the swelling of liver mitochondria, and suggest that liver mitochondria may be one of the targets for the hepatotoxic actions of cresols.