The clinical pharmacology of H1-antihistamines has not yet been optimally studied in children and other special groups of patients. Our objective was to determine the onset, extent, and duration of H1-antihistaminic activity of cetirizine and fexofenadine in the pediatric population. We performed a prospective, randomized, placebo-controlled, double-blind, crossover, single-dose study of these H1-antihistamines in 15 allergic children, mean±SEM age 8.8±0.5 years. We used suppression of the histamine-induced wheal and flare as the primary outcome. Compared with pre-dose baseline, cetirizine 10 mg suppressed the wheals significantly (p≤0.05) from 2 to 24 h and the flares significantly from 1 to 24 h, achieving 77±SEM 10% to 86±9% suppression of the wheal from 2 to 7 h and 85±6% to 88±6% suppression of the flare from 2 to 24 h, inclusive. Compared with baseline, fexofenadine 30 mg did not suppress the wheals or flares significantly at any time, achieving 40±9% to 54±9% wheal suppression from 2 to 7 h and 45±11% to 68±9% flare suppression from 2 to 7 h, inclusive. Compared with placebo, cetirizine suppressed the wheals and flares significantly from 2 to 24 h. Compared with placebo, fexofenadine suppressed the wheals significantly at 4 and 6 h, and the flares from 4 to 7 h. Cetirizine suppressed the wheals and flares significantly more than fexofenadine at 2 h (wheals), and at 3 and 24 h (flares). Placebo did not suppress the wheals and flares significantly at any time. In children age 6–11 years, cetirizine 10 mg has a rapid onset of H1-antihistaminic activity, a 24-h duration of action, and greater H1-activity than fexofenadine 30 mg. Higher doses of fexofenadine should be tested in children.