Induction of hepatic propoxyphene N-demethylase and aniline hydroxylase activities resulted following repeated oral administration of 25, 50 and 100 mg d-propoxyphene hydrochloride per kg daily in the mouse over a six-day period. A significant elevation in both enzyme activities was noted after a single dose of propoxyphene (100 mg/kg). A dose-related response characterized the observed induction of each microsomal enzyme activity. Pentobarbital sleeping times (a measure of in vivo microsomal activity) also exhibited dose-related decrements in hypnosis with increasing doses of propoxyphene. These effects appeared to correlate with the development of tolerance to both the analgesic and lethal properties of propoxyphene. Pretreatment with SKF-525A, a potent microsomal enzyme inhibitor, abolished this tolerance in each case. Furthermore, a lack of central nervous system cellular tolerance was demonstrated by the finding that intracerebroventricular LD50 values for propoxyphene in propoxyphene- and water-treated mice were identical to the value derived from naive mice. Thus, the observed tolerance seems to be the result of dispositional (metabolic) and not central nervous system tolerance.