This controlled crossover study in twenty healthy volunteer subjects utilized the citric acid aerosol-induced cough response as a means to demonstrate the effectiveness of 25 mg of diphenhydramine as an antitussive. Entry was limited to only those subjects who manifested a consistent, quantitatively definable response to a 5% citric acid challenge. Subjects were initially dosed with either a placebo vehicle or 25 mg diphenhydramine in a 10 ml formulation. Following drug ingestion, subjects were challenged at 15, 30, 45, 60, 120, and 240 minutes. Three days later, subjects were administered the alternate treatment and rechallenged at the same time points. Diphenhydramine was effective at the earliest time point assessed, 15 minutes, and continued to be as effective over the entire 4-hour duration of the test period. For the placebo vehicle, the mean cough counts did not change significantly from baseline. Neither the putative soothing effect of a liquid formulation nor accommodation to the citric acid spray can account for all the early and consistently significant activity of diphenhydramine in suppressing the cough response. The early onset of activity of diphenhydramine may be due to its local anesthetic properties or may indicate that the dose of diphenhydramine required for effective antitussive activity is lower than that required for effective antihistaminic activity. These results require further corroboration in direct comparisons of various doses of diphenhydramine with positive controls in both this model and clinical cough counting models employing pathologic cough indices. A 25 mg dose of diphenhydramine appears to be effective as an antitussive agent.