The brain is a potential target for drugs and environmental toxins. Microsomal epoxide hydrolase (mEH) is one of several critical biotransformation enzymes in xenobiotic metabolism and detoxification. In the present study, we report that the expression of mEH is significantly elevated in the hippocampus and associated cortex, but not in the cerebellum, in Alzheimer's disease (AD) patients. A large proportion of the mEH-positive cells are located around β-amyloid plaques. The mEH-positive-staining cells are astrocytes and pyramidal neurons. Western blotting analysis confirmed increased expression of mEH in AD hippocampal tissues. In primary hippocampal glial culture, β-amyloid aggregation stimulated mEH expression in the astrocytes, which displayed a patchy distribution. An environmental neurotoxic agent, trimethyl-tin, also activated mEH expression in rat hippocampus and entorhinal cortex. The present study demonstrates a significant increase in mEH expression in the AD hippocampus, a region showing abundant neuropathology in AD. The expression of mEH could also be elevated by exposure to exogenous β-amyloid in vitro and environmental toxins in vivo. Our studies suggest that mEH may play a role in pathogenesis of neurodegeneration in response to environmental stress.