The effects of dietary butylated hydroxyanisole (BHA) on the enzyme activities of glutathione (GSH) S-transferase and catechol O-methyltransferase (COMT) in the forestomach, small intestinal mucosa, and liver of Syrian golden hamsters and ICR/Ha mice were examined. GSH S-transferase activity in the hamster tissues was not enhanced appreciably after 1 or 4 weeks of feeding diets containing various concentrations of BHA. In general, short term (1 week) feeding of diets containing BHA did not differ from longer term (4 weeks) feeding of the same diets. In the forestomach of hamsters, a positive dose response on the activity of GSH S-transferase was obtained with increasing concentration of BHA in the diet for 1 or 4 weeks. The maximum effect of dietary BHA in hamsters was observed in the forestomach after 1 week of feeding, which induced an increase in GSH S-transferase activity to twice that of the control level. The same induction effect, however, was not apparent in the liver or in the small intestinal mucosa. Dietary BHA, at all concentrations studied, did not elicit any significant change in the activity of the GSH S-transferase enzyme in these two tissues. While the increase of enzyme activity in the forestomach of ICR/Ha mice was similar to that observed in the forestomach of hamsters, the induction of GSH S-transferase activity in the liver and in the small intestinal mucosa of the two animal species was drastically different. In contrast to the lack of response to dietary BHA in the hamster tissues, the induction of increased enzyme activity in the liver and intestinal mucosa of ICR/Ha mice, after 1 week of 2% BHA feeding, was greater than 7 and 11 times that of control respectively. The ineffectiveness of BHA as an enzyme inducer in the hamster tissues was similar for the activity of COMT. The enzyme activity in all three hamster tissues examined did not change significantly as a result of BHA incorporation into the diet for 1 week. In contrast, the COMT activity in the forestomach and small intestinal mucosa of the mouse was increased with increasing concentration of dietary BHA. At 2% BHA, the enzyme activity in the two tissues was 3 and 2 times that of the control level, respectively, whereas the enzyme activity in the liver remained at control level. These findings suggest that the overall unresponsiveness of detoxifying enzyme systems in the Syrian golden hamsters may be critical in the formation of forestomach tumors caused by BHA.