Exposure of phenobarbital-pretreated rats to low concentrations of halothane (0.5%) and reduced oxygen tension (FIO2 0.08) resulted in the development of liver necrosis in 51% of the animals. Fasting of rats for 24 hours before the same type of exposure increased the incidence of liver necrosis to 80%. Exposure of fed rats to enflurane (1.5%) and isoflurane (1.4%) in conjunction with low oxygen tensions resulted in no liver necrosis; however, in fasting animals, these same concentrations, when accompanied by low oxygen concentrations, produced an incidence of liver necrosis of 35% and 80%, respectively. Lower concentrations of enflurane or isoflurane failed to produce hepatotoxicity. In this study, in addition to increasing the incidence of toxicity, fasting reduced the glutathione levels and also increased cytochrome P-450 concentrations. Exposure to halothane and to isoflurane, but not to enflurane, further decreased the glutathione level. Perhaps the mechanism of liver toxicity associated with anesthesia, at least in this animal model, is related more directly to severe hypoxia than to a direct toxic intermediate produced as a result of metabolism.