Rat liver microsomal and cytosolic epoxide hydrolase may be distinguished through differences in substrate specificity: styrene 7,8-oxide is preferentially hydrolyzed by the microsomal form, while trans-stilbene oxide is the preferred substrate for cytosolic epoxide hydrolase. Large interindividual differences in the specific activity of Sprague-Dawley (outbred strain) liver cytosolic epoxide hydrolase were observed, varying from 2 to 77 pmol/min X mg protein. Interindividual variations were much lower for microsomal epoxide hydrolase. The specific activity of Fischer F-344 (inbred strain) liver cytosolic epoxide hydrolase varied only by a factor of 2. The specific activity of cytosolic epoxide hydrolase using trans-stilbene oxide as the substrate was highest in kidney and heart, followed by liver, brain, lung, testis, and spleen. For microsomal epoxide hydrolase, the specific activity was much lower in extrahepatic tissues than in liver. None of the commonly used inducers of xenobiotic metabolizing enzymes caused significant changes in rat liver cytosolic epoxide hydrolase. However, peroxisome proliferating drugs were found to drastically increase cytosolic epoxide hydrolase activity. Treatment for one week with a diet containing clofibrate (0.25%), tiadenol (0.5%) or acetylsalicylic acid (1%) caused a 8, 13 and 5 fold increase in cytosolic epoxide hydrolase activity respectively in the liver which parallelled the induction of peroxisomal beta-oxidation activity (13, 19 and 5 fold, respectively).