Recent studies suggest that histamine H2-receptor antagonists may be useful in the treatment of urticaria. This study was conducted to determine whether famotidine, a H2 antagonist, is effective in the treatment of acute urticaria and compare its effect with that of the H1 antagonist diphenhydramine. In this prospective, double-blind, controlled trial, 25 patients with urticaria of less than 72 h duration were randomized to receive a single dose of either famotidine 20 mg i.m. or diphenhydramine 50 mg i.m. Prior to treatment and 30 min after treatment, patients rated pruritus and sedation using visual analogue scales, while physicians evaluated intensity of urticaria and percentage of body surface area involved by urticaria. Famotidine was found to reduce pruritus associated with acute urticaria, intensity of urticaria, and body surface area affected by urticaria without causing sedation. Famotidine was comparable to diphenhydramine in efficacy; however, there was a (nonsignificant) trend for diphenhydramine to be more effective than famotidine in the treatment of pruritus, and for famotidine to be more effective in the reduction of surface area of involvement. It is concluded that famotidine merits further investigation as a potential medication for treatment of urticaria.