Treatment of rats with N-nitrosomorpholine (NNM) for 7 weeks led to a focal increase in liver microsomal epoxide hydrolase (EH) as early as 2 weeks after withdrawal of the carcinogen as shown by immunoperoxidase labeling. NNM treatment also leads to hyperplastic nodules and liver tumors, but much later. At the same early time point, ATPase activity was decreased in the same islands. Most of these areas already had increased ã-glutamyltranspeptidase activity. The increase in EH at this early time point was more distinct than the decrease in ATPase which has thus far been considered a suitable marker of the earliest stages in hepatocarcinogenesis. The focal increase in EH was also observed in all benign hepatomas, but not in any of the hepatocellular carcinomas investigated so far.