Recent case reports have suggested that H 2 antihistamines used alone may be effective in the treatment of acute urticaria, a common complaint of patients presenting to the emergency department. This contradicts accepted doctrine on the treatment of acute urticaria. Based on theories of H 1- and H 2-receptor interaction at the cellular level, it has been stated that H 2-blockade before H 1-blockade may exacerbate symptoms. The purpose of our study was to compare diphenhydramine, an H 1-blocker, with cimetidine, an H 2-blocker, in a randomized, prospective, double-blind clinical trial. Ninety-three patients presenting to the ED with clinical evidence of acute urticaria were treated with either 50 mg diphenhydramine IM or 300 mg cimetidine IM. Patients' signs and symptoms were quantitated on a numeric scale before receiving medications and 30 minutes after treatment. Parameters measured included degree of itching, intensity and extent of wheals, degree of sedation, and perception of overall improvement. Each medication provided significant relief of itching and wheal intensity ( P < .0001). Sedation was caused by both diphenhydramine ( P < .0001) and cimetidine ( P < .0006). However, the degree of sedation caused by diphenhydramine was significantly greater than that caused by cimetidine ( P = .0001). The perception of overall improvement was greater with cimetidine, with 87% of patients reporting improvement, whereas 76% of diphenhydramine-treated patients reported improvement. Our results indicate that cimetidine is efficacious as the initial treatment of acute urticaria and has less tendency toward sedation. Furthermore, under close observation, cimetidine did not cause any exacerbation of symptoms or untoward side effects. We advocate consideration of cimetidine as a rapid, less-sedating antihistamine for use in the initial treatment of acute urticaria.