1. Hepatic microsomal drug metabolizing activity was compared in male and female AL/N, Balb/c, Balb/cJ, CD-1, C57BL/6J, C57BL/10J, DBA/2, and DBA/2J mice. 2. Cytochrome P-450-dependent hexobarbital hydroxylase and aminopyrine N-demethylase activities were sexually dimorphic with apparent maximal velocities consistently higher in females. Hexobarbital-induced sleeping times were greater in males, corresponding to their lower hepatic mono-oxygenase enzyme activities measured in vitro. 3. No murine sex differences were observed for the hydroxylation of aniline, while UDP-glucuronyltransferase activity was strain dependent with either no sexual dimorphism or higher activities in males. 4. Testectomy resulted in an elevation of hepatic hexobarbital metabolism to female levels in all strains examined. Thus, decreased hepatic cytochrome P-450-dependent xenobiotic metabolism in adult male mice results from the suppressive effects of gonadal androgens. 5. Sexually dimorphic patterns of hepatic hexobarbital and aminopyrine metabolism in adult mice are opposite in orientation and lower in magnitude than the well established relationship in rats in which these same substrates are metabolized at a rate 3 to 5 fold higher in intact males as compared to females or gonadectomized males.