The effects of CAAD (diphenhydramine hydrochloride, 50 mg; pseudoephedrine hydrochloride, 60 mg; acetaminophen, 1 g in 10% ethanol) were evaluated in a double-blind, three-way, placebo-controlled, cross-over study on 18 volunteers with allergic rhinitis. The number of sneezes following nasal challenge with antigen was significantly reduced after a bed-time dose of CAAD (P less than .005) and a single dose of diphenhydramine (P less than .001) given 2 hours before the challenge. The levels of N-alpha-tosyl-L-arginine methyl ester (TAME) activity decreased after diphenhydramine treatment, while histamine levels following challenge were not different. The drowsiness reported after CAAD was equal to placebo, but significantly less than diphenhydramine (P less than .002 for both). The active treatments reduced the actions of histamine without suppressing its release from mast cells. The effect of CAAD persists 10 hours after administration without inducing drowsiness.