Cetirizine, a major human metabolite of hydroxyzine, preserves the histamine H1-antagonist activity of the parent compound but poorly penetrates the blood-brain barrier, thus minimizing sedative and anticholinergic effects. In 10 young (mean age 27.7 years) subjects with mild asthma (FEV1 greater than 70% predicted), we evaluated the bronchodilator and protective efficacy of 5, 10, and 20 mg of cetirizine against bronchospasm induced by histamine inhalation (0.03 to 20 mg/ml) in comparison with placebo and hydroxyzine, 25 mg, using a random, double-blind crossover design. The provocative concentration of histamine causing a 20% decline in FEV1 for all 10 subjects from the postdiluent control value was more than fourfold greater after each active drug than after placebo. Cetirizine, 5 to 20 mg, provided significantly greater protection against histamine-induced bronchospasm than hydroxyzine (p less than 0.001); moreover, a dose-dependent protective effect was noted with cetirizine. Significant bronchodilation was also found: at 60 minutes, FEV1 increased significantly after all active antihistamines compared to placebo and after 20 mg of cetirizine compared to hydroxyzine (p less than 0.05). FEV1 increased significantly at 120 minutes after hydroxyzine and after cetirizine in both the 20 and 10 mg doses compared to placebo (p less than 0.05). We conclude that in subjects with mild asthma, orally administered cetirizine provides significant dose-dependent protection against histamine-induced bronchoconstriction, which in the doses studied is superior to that produced by the parent compound, hydroxyzine. In addition, cetirizine in 5 to 20 mg doses causes acute bronchodilation. These results suggest a possible role of cetirizine in asthma therapy.