It has often been observed that chemical-induced initial insult is no longer detected in examinations after additional consecutive treatments, suggesting that the target organs acquire resistance to chemical toxicity. In this study, we examined whether acquired resistance to toxicity would be observed after repeated treatments of a toxic dose of bromobenzene (BB). In Experiment 1, F344 male rats were intraperitoneally given BB at a dosage of 150 mg/kg/day. Based on the serum AST level 20 h after the first treatment, the rats were divided into 2 groups, Groups 2 and 3, which consisted of rats with elevated AST and rats without remarkable changes in AST activity, respectively. Subsequently, the rats were subjected to the same BB treatment regimen for 4 or 9 consecutive days. The control group (Group 1) was administered with the vehicle. The AST activity of Group 2 showed no remarkable changes from Day 3, indicating an acquired resistance to BB hepatotoxicity. Measurements of drug-metabolizing enzymes in Group 2 demonstrated a reduction in CYP contents and activities, and a strong induction of GST, which contributed to the resistance. The aminotransferase activities in Group 3, however, showed no changes throughout the dosing periods. In Experiment 2, the rats with the same BB treatment regimen as Experiment 1 were administered intraperitoneally with a single dosage of BB of 300 mg/kg. Although a higher dosing of BB caused hepatic injury in all three groups, the degree of injury in the two groups with BB treatment was much slighter than that in the control (vehicle + BB). These results indicate that not only Group 2 but also Group 3 acquired resistance to BB hepatotoxicity after repeated treatments. The exposure levels of BB in the two groups were lower than those of the control. Thus, changes in the drug-metabolizing reaction related to the metabolism and detoxification of BB contributed to the resistance to BB hepatotoxicity.