The effect of salicylamide and acetaminophen on the metabolic fate of dextrorphan, the primary metabolite of dextromethorphan, was studied in vivo in the rat. Plasma dextrorphan levels were measured at 5-min intervals up to 20 min and at longer intervals up to 2 hr after dextromethorphan hydrobromide was administered orally either alone or in combination with salicylamide and acetaminophen. The combination gave rise to higher plasma dextrorphan levels than did dextromethorphan hydrobromide alone at most sampling times. Conjugation of dextrorphan was inhibited almost quantitatively by salicylamide and acetaminophen at the 5-min sampling time. Salicylamide alone increased the plasma dextrorphan levels when it was coadministered with dextromethorphan, but the differences were not statistically significant. The antitussive activity of dextromethorphan hydrobromide in the unanesthetized dog was faster in onset, greater in intensity, and longer in duration when it was coadministered with salicylamide and acetaminophen. It is suggested that salicylamide and acetaminophen may inhibit the metabolic inactivation of dextrorphan, thereby improving the coughinhibiting potential of dextromethorphan hydrobromide.