Cholesterol epoxide hydrolase (mCE) is a microsomal enzyme that hydrolyzes cholesterol-5,6-epoxides (CE) to cholestanetriol (CT). In the present study, hepatic mCE activity was measured in mice pretreated with several different xenobiotics known to induce a variety of hepatic drug-metabolizing enzymes. Only the phenoxyacetate hypolipidemics (clofibrate and ciprofibrate, included in the diet for 14 days) were found to increase hepatic mCE activity (1.8-fold increase). Clofibrate administration also increased rabbit hepatic (2.9-fold increase) and rat and rabbit renal mCE activity (1.5- and 2.3-fold increase respectively). On a subcellular level, mCE activities in rabbit nuclear and light mitochondrial fractions were increased (3.3- and 1.8-fold increase respectively), whereas activities in the cytosolic and heavy mitochondrial fractions were unchanged. In rabbits, clofibrate administration enhanced the hepatic microsomal hydrolysis of CE without increasing the hydrolysis of arene epoxides (benzopyrene-4,5-oxide) or fatty acid epoxides (methyl cis-9,10-epoxystearate). Increase of tissue mCE activity may significantly enhance tissue CT levels. In this light, it is worth noting similarities in the mechanisms of hypocholesterolemic action caused by clofibrate or CT administration.