Rats or mice developed centrolobular hepatic necrosis within 24 h after an intraperitoneal injection of 14C-bromobenzene or other radiolabeled halogenated aromatic hydrocarbons. The hepatic necrosis was preceded by the cova lent binding of substantial amounts of radiolabeled material to liver proteins, and autoradiograms revealed that most of the covalently bound material was localized within the necrotic centrolobular hepatocytes. Prior induction of hepatic microsomal enzymes by phenobarbital administration potentiated the covalent binding and necrosis, whereas prior inhibition of hydrocarbon metabolism had the opposite effects, suggesting that the binding and necrosis are caused by toxic metabolites of the hydrocarbons. These results imply that covalent binding of toxic metabolites may be an important mechanism in the pathogenesis of tissue lesions elicited by a variety of foreign compounds.