The effects of hepatic microsomal enzyme induction with phenobarbital and depletion of hepatic glutathions (CSH) with diethyl maleats on the acute hepatotoxic responses to chloroform and halothane anesthesia were studied in rats. Phenobarbital pretreatment markedly increased the hepatotoxic response to chloroform anesthesia, but had little effect on halothane hepatotoxicity. Hepatic CSH levels were decreased 70–80 per cent by 2 hour* of Chloroform anesthesia in induced rats, but were unchanged in non-induced rats and in animals anesthetized with halothane. Marked destruction of microsomal electron transfer components was observed in the chloroform-anesthetized, induced animals only. Induction caused a large increase in in-vitro covalent binding of 14CHCl3 metabolites to microsomal protein, which could be prevented by CSH. Diethyl maleate pretreatment lowers CSH content approximately 80 per cent. Chloroform anesthesia produced hepatic necrosis and destruction of microsomal enzymes in the absence of induction, but halothane did not. Hepatotoxicity of chloroform appears to be related to two factors: 1) rate of biotransformation; 2) availability of the hepatic antioxidant, CSH. Halothane hepatotoxicity does not proceed by the same sequence of events as does that of chloroform.