Exposure of triiodothyronine (T3-pretreated rats to 1.3% isoflurane 1.8% enflurane, or 1% halothane in 21% oxygen (air) for two hours resulted in hepatic centrilobular necrosis. The incidence of the liver lesion was 28, 24, and 92% after exposure to isoflurane, enflurane, and halothane, respectively. Histopathologic grading indicated that the necrosis was more severe after halothane than after isoflurane or enflurane anesthesia. No lesion was observed in livers prepared from non-anesthetized T3-pretreated rats or in livers prepared from rats which were pretreated with the vehicle for T3and then anesthetized with either isoflurane, enflurane, or halothane. Hepatic necrosis was not observed in vehicle-treated rats exposed to isoflurane in 12% oxygen or in vehicle-treated rats that were deprived of food for 12 hours prior to exposure to isoflurane under hypoxic conditions. Food restriction to maintain the body weight gain of vehicle-treated rats similar to that of T3-treated rats did not result in hepatotoxicity after exposure to halothane in 21% oxygen. Liver necrosis did not occur in pentobarbital anesthetized (40 mg/kg, intraperitoneally) T3-pretreated rats. These results indicate that isoflurane and enflurane, like halothane, can induce hepatic centrilobular necrosis in T3-pretreated rats. The mechanism for liver toxicity of these volatile anesthetic agents in this model remains to be determined.