Abstract Withdrawal reactions were compared in C57BL/6J mice, which had been fed an ethanolic liquid diet containing chloridazepoxide (CDP, 3.2 or 6.4 mg/100 ml, group B or C, respectively) with those which had been administered an ethanol diet alone (group A) for 15 days. Group A showed a significantly more pronounced decrease in rectal temperature (4 to 10 hr) and a higher withdrawal score (4 to 14 hr) than mice in groups B and C. The differences in withdrawal signs still persisted even after mice were fed an ethanol diet without CDP for one extra day before withdrawal. The presence of metabolites of CDP in the blood during withdrawal could only account for a minor contribution to the protective effect. Our data are more suggestive of an increased rate of ethanol metabolism leading to lower blood alcohol levels during diet intake period as being the major factor. However, we cannot rule out the alternative possibility that CDP or its metabolites might interfere with the development of tolerance to and physical dependence on alcohol.