This study was designed to investigate sex differences in halothane metabolism and hepatotoxicity in the hypoxic rat model. Phenobarbital-induced male and female rats were anesthetized with 1% halothane in 14% oxygen for two hours. Female rats were found to metabolize halothane by the oxidative pathway to a similar extent as males, but the extent of metabolism by the reductive pathway was less in females. All male rats exposed under these conditions developed confluent centrilobular hepatic necrosis. Females were less susceptible than males to the hepatotoxic effect of halothane, with responses ranging from no hepatic injury to confluent centrilobular necrosis limited to within a few cells of the central veins. This lesser susceptibility was not, however, solely due to the lesser extent of reductive metabolism in females, as lowering the inspired oxygen concentration to 12% increased the extent of reductive metabolism but did not increase the severity of the hepatic injury.