The metabolism of hydrocodone was studied in man, rat, guinea pig, rabbit, and dog. Routes of metabolism included O-demethylation, N-dealkylation, and 6-keto-reduction to the corresponding 6-alpha- and 6-beta-hydroxy metabolites, where each metabolic pathway produces an active metabolite. Mean total recovery of drug and metabolites as percentage of administered dose ranged from a low of 10.6% for the rabbit to a high of 46.8% for the guinea pig; man was intermediate at 25.7%. For man, approximately 70% of the total drug recovered was excreted in the first 24 hr, and the remainder by 72 hr. Considerable species differences were observed in the patterns of metabolism of hydrocodone. Also, stereoselectivity of 6-keto reduction to the beta-form was observed for all species in the reduction of hydrocodone and hydromorphone with the exception of the reduction of hydrocodone by man.