SummaryTritium-labeled diphenhydramine given iv to rhesus monkeys produced a rapid drop in plasma levels of unchanged drug, but the total tritium activity rose slowly over a 4-hr period to levels severalfold greater than those observed 1 min after dosing. This was attributed to rapid removal of drug by the tissues, followed by a slow return of metabolites to the plasma. The major metabolite, strongly bound to plasma protein, was identified as diphenylmethoxyacetic acid. Similar observations were made in the dog, rabbit, guinea pig, and mouse; but not in the rat, which did not form diphenylmethoxyacetic acid. Species differences were noted in the conjugation of this metabolite with glutamine in the monkey, and with glycine in the dog.